TW200914822A - Sensor system based on compound with solubility depending on analyte concentration - Google Patents
Sensor system based on compound with solubility depending on analyte concentration Download PDFInfo
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- TW200914822A TW200914822A TW97115995A TW97115995A TW200914822A TW 200914822 A TW200914822 A TW 200914822A TW 97115995 A TW97115995 A TW 97115995A TW 97115995 A TW97115995 A TW 97115995A TW 200914822 A TW200914822 A TW 200914822A
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Abstract
Description
200914822 九、發明說明: 【發明所屬之技術領域】 本發明係關於一種測定存在於一液體中分析物濃度之方 法,更特定言之,關於一種利用或包括具有基於分析物濃 度的可變溶解度的化合物之感測系統。 【先前技術】 一生物流體中的分析物濃度既可藉由量化一對目標分析 物具有特異之化學相互作用或藉由將一分析物轉換成可測 f) 的物理參數進行測定。例如,一流體的pH可藉由滴定(化 學反應)或使用將H+濃度轉化成電位的pH計進行測定。 一傳統的pH計使用兩個玻璃電極:指示電極與參考電 極。當兩個電極浸入一溶液中,形成了一小型化學電池。 所發展出的電位與兩個電極相關。該反應由在兩種溶液中 的H+濃度所控制的離子交換中玻璃離子與溶液之h+在膨 潤薄膜表面之交換所引起》傳統的pH感測技術可縮小化至 某一尺寸以測定活體内的pH值並遙測報告資料。 ϋ 另一PH感測技術係基於使用一離子敏感場效應電晶體 (ISFET)。在一 ISFET中,一 U+敏感緩衝塗層塗於閘極。因 此,漏極與源極之間的電壓壓降變成閘極所暴露之一H+濃 度之函數。一基於181^1的1?11感測器可做成小體積。實驗 至ISFET pH感測器可從市場上購得且通常比傳統玻璃電極 pH感測器昂貴。 傳統的基於玻璃電極的pH感測技術實際上不能縮小化至 適於電子藥丸之尺寸。傳統的與基於ISFET的pH感測器 130412.doc 200914822 均需要校準及參考電極,使其使用變得複雜。藉由一 ISFET pH感測器測定之pH精度可負面地受11+以外的離子 例如食鹽的離子影響。目前ISFET成本比較高。此外,所 有現用的PH感測器之絕對眞之精度與再現性取決於精 確與及時的校準’這使其等之部署變得昂貴且繁複。 對於胃腸(GI)道之即時料u,在胃腸道中運輸期 間-PH感測器必須在活體内操作,並㈣非常小的體積, 同時絕對精度不那麼嚴格,可回收性並非—必要條件。 除了 pH’其他分析物諸如蛋白質、胺基酸、葡萄糖、酶 及其類似物之濃度亦具有較大診斷價值。雖然,上述分析 物可在活體外用實驗室裝置測定,但測定蛋白質或酶濃度 的實用活體内方法及/或裝置無法從市場上購得。 在生物醫學領域,活體内測定可提供即時與就地資訊。 然而’要求活體内方法係生物相纟#,以便該方法之製程 與副產物不干涉生物系統的自然運作。此外,由於器官之 自…:尺寸任何引入活體内的裝置及/或組件必須足夠小 以適應生物感測區域。 儘管迄今為止的嘗試,對測定分析物濃度的有效方法與 系統仍有需求,特別在生物醫學應用方面,例如活體内應 用。該等及其他需求彳由此處揭示的方法與系統獲得滿 足。 【發明内容】 根據本揭示内容提供一種用於生化測定的生化感測裝置 與方法。所揭示感測的裝置與方法可在活體内使用以測定 130412.doc 200914822 分析物含量。例如’可使用所揭示的感測裝置與方法以測 定H+濃度(即pH)、蛋白質、胺基酸、葡萄糖、酶及其他所 關心的分析物。200914822 IX. DESCRIPTION OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to a method for determining the concentration of an analyte present in a liquid, and more particularly to a use or inclusion of a variable solubility based on the concentration of the analyte. Compound sensing system. [Prior Art] The concentration of an analyte in a biological fluid can be determined either by quantifying a specific chemical interaction of a pair of target analytes or by converting an analyte into a physical parameter of measurable f). For example, the pH of a fluid can be determined by titration (chemical reaction) or using a pH meter that converts the H+ concentration to a potential. A conventional pH meter uses two glass electrodes: the indicator electrode and the reference electrode. When the two electrodes are immersed in a solution, a small chemical battery is formed. The potential developed is related to the two electrodes. The reaction is caused by the exchange of glass ions and the h+ of the solution on the surface of the swollen film in the ion exchange controlled by the H+ concentration in the two solutions. The conventional pH sensing technique can be reduced to a certain size to determine the in vivo. pH and telemetry report data.另一个 Another PH sensing technology is based on the use of an ion-sensitive field effect transistor (ISFET). In an ISFET, a U+ sensitive buffer coating is applied to the gate. Therefore, the voltage drop across the drain and source becomes a function of the H+ concentration at which the gate is exposed. A 1?11 sensor based on 181^1 can be made into a small volume. Experiments to ISFET pH sensors are commercially available and are generally more expensive than conventional glass electrode pH sensors. Conventional glass-based pH sensing techniques cannot actually be scaled down to the size of electronic pills. Both conventional and ISFET-based pH sensors 130412.doc 200914822 require calibration and reference electrodes to complicate their use. The pH accuracy as measured by an ISFET pH sensor can be negatively affected by ions other than 11+ such as salt. At present, ISFET costs are relatively high. In addition, the absolute accuracy and reproducibility of all current PH sensors depends on accurate and timely calibration, which makes their deployment expensive and cumbersome. For the immediate delivery of the gastrointestinal (GI) tract, the PH sensor must be operated in vivo during transport in the gastrointestinal tract, and (iv) a very small volume, while the absolute accuracy is less stringent, and recyclability is not a necessary condition. In addition to the pH' other analytes such as proteins, amino acids, glucose, enzymes and their analogs, the concentration is also of great diagnostic value. Although the above analytes can be assayed in vitro using laboratory equipment, practical in vivo methods and/or devices for determining protein or enzyme concentrations are not commercially available. In the biomedical field, in vivo measurements provide immediate and local information. However, the in vivo method is required to be a biological phase so that the process and by-products of the method do not interfere with the natural operation of the biological system. In addition, any device and/or component introduced into the living body must be small enough to accommodate the biosensing area due to the size of the organ. Despite attempts to date, there is still a need for effective methods and systems for determining analyte concentrations, particularly in biomedical applications, such as in vivo applications. These and other needs are met by the methods and systems disclosed herein. SUMMARY OF THE INVENTION A biochemical sensing device and method for biochemical assays is provided in accordance with the present disclosure. The disclosed sensing devices and methods can be used in vivo to determine the analyte content of 130412.doc 200914822. For example, the disclosed sensing devices and methods can be used to determine H+ concentrations (i.e., pH), proteins, amino acids, glucose, enzymes, and other analytes of interest.
在本揭不内容之示範性具體實施例中,所提供的感測裝 置包括一電極(12)、一連接到電極的電源(丨8)及一在電極 上的化合物塗層(14)。該化合物可溶於一分析物溶液中, 其溶解度速率取決於該分析物之濃度,藉此可使得在一特 定環境中定量分析物含量.該生化感測裝置可進一步包括 一在電源與電極之間的連接處的電開關(16)。該生化感測 裝置可進一步包括一連接到電源(18)的資料處理器(22), 及一連接到資料處理器的資料記憶體組件(24)。 亦提供一種測定一溶液的分析物濃度之方法。在本發明 之示範性具體實施例中,所揭示的方法包括提供—用一化 合物塗布的電極,丨中該化合物具有分析物濃度相關的溶 解度分佈,將該經塗布之電極暴露於溶液巾,測定阻抗速 率作為-時間函數’且使阻抗速率與化合物溶解度相互關 聯以確定溶液之分析物濃度。 -根據本揭示内容之生化感測裝置之實例係—pH感測裳 置。所揭示的感測裝置與方法的另外的有利的特色、功能 及應用將由以下描述闡明。 【實施方式】 本文揭示之系統及方 爲助於熟悉本技藝者製造及使用 法’將參考附圖加以說明。 本發明提供一種尺寸小型化 製造上經濟、便於部署且 130412.doc 200914822 物相谷的生化感測系統。所揭示的生化感測器系統之示 範&只施例包括至少_對由一化合物(例如—聚合物)包覆 的電極二其中該化合物的溶解度與—生化分析物的濃度相 關。當藉由所述化合物/聚合物塗布的電極暴露至一溶液 時,電極之間的電導阻抗以化合物/聚合物在溶液中的溶 解度作為函數而變化。至化合物/聚合物溶於溶液的程度 下,試樣溶液填滿藉由溶解化合物/聚合物產生的空隙:In an exemplary embodiment of the present disclosure, a sensing device is provided that includes an electrode (12), a power source (丨8) coupled to the electrode, and a compound coating (14) on the electrode. The compound is soluble in an analyte solution, the rate of solubility of which depends on the concentration of the analyte, thereby allowing the analyte content to be quantified in a particular environment. The biosensing device can further comprise a source and an electrode Electrical switch (16) at the junction. The biochemical sensing device can further include a data processor (22) coupled to the power source (18), and a data memory component (24) coupled to the data processor. A method of determining the analyte concentration of a solution is also provided. In an exemplary embodiment of the invention, the disclosed method comprises providing an electrode coated with a compound having a solubility profile associated with an analyte concentration, exposing the coated electrode to a solution towel, determining The impedance rate acts as a function of time and correlates the impedance rate with the solubility of the compound to determine the analyte concentration of the solution. - An example of a biochemical sensing device according to the present disclosure is a pH sensing skirt. Further advantageous features, functions, and applications of the disclosed sensing devices and methods will be clarified by the following description. [Embodiment] The system and the methods disclosed herein will be described with reference to the accompanying drawings. The present invention provides a biochemical sensing system that is small in size and economical to manufacture, and that is easy to deploy and has a phase of 130412.doc 200914822. Exemplary of the disclosed biochemical sensor system & only examples include at least one electrode coated with a compound (e.g., a polymer) wherein the solubility of the compound is related to the concentration of the biochemical analyte. When the electrode coated with the compound/polymer is exposed to a solution, the conductance impedance between the electrodes varies as a function of the solubility of the compound/polymer in solution. To the extent that the compound/polymer is dissolved in the solution, the sample solution fills the void created by dissolving the compound/polymer:
因為化合物/聚合物與溶液相比係不良導體,電極上的化 物聚、σ物塗層之溶解導致電極之間導電增大。電導變 化速率進—步取決於化合物/聚合物性質與試樣溶液的實 際分析物濃度》 適用於根據本揭示内容之塗布電極之材料包括顯示出溶 解度取决於所關心的生化材料(例如η+濃度(即洲、蛋白 邊胺基酉夂、冑肖糖、酶及其他所_心' 的分析物)濃度之 市σ材料用於根據本揭示内容之塗布電極之示範性材料 包括顯示出-與ρΗ相關之溶解速率的聚合物,諸如 egussa GmbH有限公司製造的EUDRAGIT丙烯酸聚合物, 以及顯不出與結腸酶存在相關之溶解速率之聚合物,諸如 yme plc A司(英國劍橋)所用的偶氮聚合物。所述聚合 物已使用作為標說藥私^ & 从 桌物傳輸之樂丸上之塗層。然而,根據 本揭7F内☆’使用具有提及的性質的材料係有利地用作電 極塗層。 方法在本文將參考pH 所揭示的系統與方法 為了說明之目的,所揭示的系統與 相關實施更詳細地進行插述。然而, 130412.doc 200914822 具有廣範圍適用性,其對熟習此項技術人士顯而易見,包 括針對各種分析物的實施。因此,在_本揭示内容之示範 性具體實施例令’該系統包括在pH高於閣值之前並不溶解 的電極塗布化合物/聚合物,且因此電極之間的電導在試 樣溶液具有一高於此閾值的pH之前並不會增大。如果試樣 溶液之pH高於該應用的閾值,則電極之間的電導將有利地 隨試樣的實際pH值與聚合物的閾值pH之間之差異按比例 增加。 此外,如果塗布在電極上的化合物/聚合物在溶液2pH 低於閾值之前並不溶解,則電極之間的電導在溶液具有一 低於此閾值的pH之前並不增大且如果溶液的pH值低於閾 值,則電導將根據溶液的實際pH值與閾值間之差異按比例 增大。因此,藉由監測以該化合物/聚合物覆蓋的電極之 間的電導變化率,可導出pH極限值或實際pH值。 當使用基於與pH之溶解度相關理論之pH感測器時,各 對電極之間電導作為一時間函數進行測定,使用電導變化 速率以導出溶液之PH值。此類pH感測器系統的一個獨特 優點係可無須校準地進行操作。製造製程與環境條件之變 化(諸如試樣溶液的總電導率)可引起電極之間的絕對電導 之變化。然而,該等變化並不干擾試樣溶液pH值之導出, 此係因為pH值係藉由電導之變化率予以測定,而非藉由電 導之絕對值予以測定。當然,此類系統可結合與參考電極 一起使用以考量電導率之環境變化。 如圊1所示,一種根據本揭示内容之示範性pH感測器包 130412.doc 200914822 括以化σ物/聚合物14覆蓋的一對電極12與12,; 一定時 = = 16; —交替頻率介於1〇〇沿與】Mhz的交流電源18; 為料地里“ 22、一 s己憶體24,其儲存介於電極間所測之 電導值及針對電導變化梯度與其對應值的查找表;以 及報口或顯示- pH值的組件26。該開關i 6按一給定時間 間隔而開啟與關閉介於交流電源與電極之間的連接。通過 電極的電流被測定、由資料處理器予以轉換成對應的電導 賴存在記憶體中。資料處理器計算電導變化梯度,並將 纟與查找表中用於該化合物/聚合物的值相比較,並報告 試樣溶液10的當前的pH值。 電極可為任何適當的組態,無須為所示的平板,可採用 任何便利的形狀與佈置。此外,可使用一系統時鐘使資料 流與處理同步。 在-具體實施例中,該pH感測裝置包括一電極對12、 12’、一連接15至電極對12、12,的電源“及一在至少一電 〇 極上的化合物/聚合物塗層14。該聚合物係可溶於一溶液 中,/合解度速率可取決於溶液的pH。纟另_ #體實施例 中,PH感測裝置可進一步包括一在電源_電極對12、 12’之間的連接處的電開關16。此外,PH感測裝置可包括 ·-連接20到電源18的資料處理㈣,與—連接到資料處理 器的資料記憶體組件24。 在-示範性具體實施例中,該pH感測器包括一對用一溶 於PH在約2與約6.5之間的溶液中的化合物/聚合物包覆之 電極。H+離子之存在可影響特定化合物/聚合物之溶解 130412.doc -11 - 200914822 度,例如通常用作藥物上之腸衣的聚合物。上述聚合物之 實例係用於塗布藥物劑型之合成丙烯酸聚合物,其商標名 稱 EUDRAGIT(德國 Rohm GmbH有限公司)。EUDRAGIT 聚 合物之溶解度性質取決於溶液條件,特別是溶液的pH值。 腸溶衣係特別設計以具有與消化道所需階段相容之溶解度 性質。例如,EUDRAGIT L100在pH值高於6.0(溶解的pH 閾值)之前不溶於水流體中且pH 6.1至pH 7.1時其溶解速率 可提高10倍。此外,上述聚合物之特性係儲存期間對環境 〇 影響的高穩定性及對皮膚無害,即對身體組織與體液無作 用(參見"醫藥劑型用EUDRAGIT薄膜包衣實用課程π, Rohm GmbH有限公司,德國,2001年)。該等聚合物在其 處於固態時係不良電導體。 適用於pH感測裝置的EUDRAGIT聚合物包括曱基丙烯酸 聚合物、曱基丙烯酸酯聚合物、甲基丙烯酸胺烷基酯聚合 物及甲基丙烯酸銨烷基酯聚合物。除了 EUDRAGIT聚合物 之外,用於本揭示内容之pH相關實施適當的聚合物包括任 〇 何具有與pH-相關之溶解度之聚合物。適當的聚合物包括 聚鄰苯二甲酸醋酸乙烯酯聚合物、鄰苯二曱酸羥丙基甲基 纖維素酯聚合物、苯三曱酸醋酸纖維素酯聚合物及苯二甲 .酸醋酸纖維素酯聚合物。 此外適用於本揭示内容所揭示的pH感測裝置係具有介於 約5與約7的閾值pH之化合物/聚合物,其意指化合物/聚合 物在pH介於約5與約7的溶液中溶解。另,具有介於約4與 約6的閾值pH的化合物/聚合物亦適用,且上述化合物/聚 130412.doc •12· 200914822 物/合於pH介於約4與約6的溶液中。此外,所用的化合物 /聚口物可溶於pH介於約2與約6 5之溶液。該化合物/聚合 物可具有適於應用之溶解度速率,因此速率不至於快至難 以測定速率及/或需要特別厚的化合物/聚合物塗層,也不 至於溶解得過慢以致於難以在短時間内測定電導之變化。 最好,該等化合物/聚合物具有大於約i毫米/ι〇〇分鐘的最 大溶解度速率。同樣地,該等化合物/聚合物最好具有一 擴大10倍的溶解度速率之範圍,因此在該閾值?11’該化合 物/聚合物以1微米每分鐘之速率溶解且該速率提高至一最 大值約20微米每分鐘。 為了涵蓋比用單一化合物/聚合物可達到的ρΗ·圍更寬 的pH範圍,可根據本揭示内容有利地將多對電極用於單個 pH感測器系統中,各個電極用一具有溶解閾值之化合 物/聚合物包覆。在另一根據本揭示内容之具體實施例 中,提供了一種pH感測器,其包括一對以上的電極,且以 一具有不同的溶解pH閾值之化合物/聚合物塗布各對電 極0 因此’此處揭示了一種pH感測器,其中以具有pH閾值 與另一對電極不同的化合物/聚合物塗布兩對或兩對以上 的電極。利用一對以上以具有不同pH閾值的化合物/聚合 物塗布的電極,所揭示的pH感測器可感測更寬範圍的pH 並獲得更佳的精度。例如,可將電極指定用於檢測消化道 (包括胃與腸,其具有不同pH範圍)不同區域的pH。在一應 用中諸如一可攝取的藥丸,pH感測器可具有專門用於檢測 130412.doc -13· 200914822 存在於胃t的低PH值的電極,而具有在上述低pH值下不 溶解的化合物/聚合物的電極在感測器到達腸的較高阳區 域剛保持完整無損。 如圖2所示,係一具有以第一化合物/聚合物28塗布的第 一對電極25、25,的示範性PH感測器。該裝置進而包括以 第二化合物/聚合物30塗布的第二對電極29、Μ,。第二化 合物:聚合物係可溶於一溶液中,其溶解度速率可取決於 該溶液的pH。在一且辦音a丨上 ..Since the compound/polymer is a poor conductor compared to the solution, the dissolution of the chemical on the electrode and the dissolution of the σ coating results in an increase in conductivity between the electrodes. Conductivity change rate further depends on compound/polymer properties and actual analyte concentration of the sample solution. Materials suitable for coating electrodes according to the present disclosure include exhibiting solubility depending on the biochemical material of interest (eg, η+ concentration) (Immediately, the protein of the amino acid, the flavonoids, the enzymes, and other analytes) concentration of the material σ material for the exemplary materials of the coated electrode according to the present disclosure includes the display of - and ρΗ Related dissolution rate polymers, such as EUDRAGIT acrylic polymers manufactured by egussa GmbH, and polymers exhibiting dissolution rates associated with the presence of colonic enzymes, such as azo polymerization used by yme plc A (Cambridge, UK) The polymer has been used as a coating for coating on a musical tablet that is transported from a table. However, according to the present invention, the use of materials having the properties mentioned is advantageously used as Electrode coating. Methods The systems and methods disclosed herein with reference to pH are disclosed in more detail for the purposes of illustration. 130412.doc 200914822 has a wide range of applicability, which will be apparent to those skilled in the art, including the practice of various analytes. Thus, in an exemplary embodiment of the present disclosure, the system is included at a higher pH. Electrode coating compound/polymer that does not dissolve before the value, and therefore the conductance between the electrodes does not increase until the sample solution has a pH above this threshold. If the pH of the sample solution is higher than the application The threshold, then the conductance between the electrodes will advantageously increase proportionally with the difference between the actual pH of the sample and the threshold pH of the polymer. Furthermore, if the compound/polymer coated on the electrode is below pH in solution 2 If the threshold does not dissolve before, the conductance between the electrodes does not increase until the solution has a pH below this threshold. If the pH of the solution is below the threshold, the conductance will be based on the actual pH of the solution and the threshold. The difference increases proportionally. Therefore, by monitoring the rate of conductance change between the electrodes covered with the compound/polymer, the pH limit or the actual pH can be derived. In the pH-dependent theoretical pH sensor of pH, the conductance between each pair of electrodes is measured as a function of time, and the rate of change in conductance is used to derive the pH of the solution. A unique advantage of such a pH sensor system is not required. Calibrating operation. Variations in the manufacturing process and environmental conditions (such as the total conductivity of the sample solution) can cause changes in the absolute conductance between the electrodes. However, such changes do not interfere with the derivation of the pH of the sample solution. This is because the pH is determined by the rate of change of conductance rather than by the absolute value of the conductance. Of course, such systems can be used in conjunction with a reference electrode to account for environmental changes in conductivity. An exemplary pH sensor package 130412.doc 200914822 in accordance with the present disclosure includes a pair of electrodes 12 and 12 covered with a sigma/polymer 14,; a certain time == 16; - an alternating frequency between 1 〇交流 along with the Mhz AC power supply 18; in the material field "22, a s memory 24, which stores the measured conductance value between the electrodes and a look-up table for the conductivity change gradient and its corresponding value; Message or display port - the pH of the assembly 26. The switch i 6 turns the connection between the AC power source and the electrode on and off at a given time interval. The current through the electrodes is measured and converted by the data processor into corresponding electrical conductance in the memory. The data processor calculates the conductance change gradient and compares 纟 to the value for the compound/polymer in the lookup table and reports the current pH of sample solution 10. The electrodes can be of any suitable configuration, without the need for a flat plate as shown, in any convenient shape and arrangement. In addition, a system clock can be used to synchronize the data stream with the processing. In a specific embodiment, the pH sensing device includes a pair of electrodes 12, 12', a connection 15 to the pair of electrodes 12, 12, and a compound/polymer coating 14 on at least one of the electrodes. The polymer is soluble in a solution, and the rate of resolution may depend on the pH of the solution. In other embodiments, the pH sensing device may further include a pair of power source electrodes 12, 12' The electrical switch 16 between the connections. In addition, the PH sensing device can include a data processing (4) for connecting 20 to the power source 18, and a data memory component 24 connected to the data processor. - Exemplary implementation In one embodiment, the pH sensor comprises a pair of compound/polymer coated electrodes dissolved in a solution having a pH between about 2 and about 6.5. The presence of H+ ions can affect the dissolution of a particular compound/polymer. 130412.doc -11 - 200914822 degrees, for example, a polymer commonly used as a casing for pharmaceuticals. Examples of the above polymers are synthetic acrylic polymers for coating pharmaceutical dosage forms under the trade name EUDRAGIT (Rohm GmbH, Germany). EUDRAGIT polymer solubility The quality depends on the solution conditions, in particular the pH of the solution. The enteric coating is specially designed to have solubility properties compatible with the desired stage of the digestive tract. For example, EUDRAGIT L100 is before pH above 6.0 (dissolved pH threshold) It is insoluble in water and has a 10-fold increase in dissolution rate from pH 6.1 to pH 7.1. In addition, the properties of the above polymers are highly stable to the environment during storage and are not harmful to the skin, ie no to body tissues and body fluids. Role (see "Ultra DRAGIT film coating practical course for pharmaceutical dosage forms π, Rohm GmbH, Germany, 2001). These polymers are poor electrical conductors when they are in solid state. EUDRAGIT polymerization for pH sensing devices The composition includes a mercaptoacrylic acid polymer, a mercaptoacrylate polymer, an aminoalkyl methacrylate polymer, and an ammonium alkyl methacrylate polymer. In addition to the EUDRAGIT polymer, it is used in the pH correlation of the present disclosure. The implementation of suitable polymers includes any polymer having a pH-related solubility. Suitable polymers include poly(vinyl acetate) polymerization of vinyl phthalate. , hydroxypropyl methyl cellulose phthalate polymer, cellulose acetate phthalate polymer and cellulose acetate polymer. Also suitable for the pH disclosed in the present disclosure The sensing device is a compound/polymer having a threshold pH of between about 5 and about 7, which means that the compound/polymer dissolves in a solution having a pH between about 5 and about 7. In addition, having a ratio of about 4 to A compound/polymer of a threshold pH of about 6 is also suitable, and the above compound/poly 130412.doc •12·200914822 is/combined in a solution having a pH between about 4 and about 6. In addition, the compound/polymer used is soluble in a solution having a pH between about 2 and about 65. The compound/polymer may have a solubility rate suitable for the application, so the rate is not so fast that it is difficult to measure the rate and/or a particularly thick compound/polymer coating is required, nor is it too slow to dissolve so that it is difficult in a short time The change in conductance is measured internally. Preferably, the compounds/polymers have a maximum solubility rate of greater than about i mm / ι 〇〇. Similarly, the compounds/polymers preferably have a range of solubility rates that are 10 times greater, and therefore at this threshold? The 11' compound/polymer dissolves at a rate of 1 micron per minute and the rate is increased to a maximum of about 20 microns per minute. In order to encompass a wider pH range than can be achieved with a single compound/polymer, multiple pairs of electrodes can advantageously be used in a single pH sensor system in accordance with the present disclosure, each having a dissolution threshold Compound/polymer coating. In another embodiment in accordance with the present disclosure, a pH sensor is provided that includes a pair of electrodes and that coats each pair of electrodes with a compound/polymer having a different solubility pH threshold. Disclosed herein is a pH sensor in which two or more pairs of electrodes are coated with a compound/polymer having a pH threshold different from another pair of electrodes. Using a pair of electrodes coated with a compound/polymer having different pH thresholds, the disclosed pH sensor can sense a wider range of pH and achieve better accuracy. For example, electrodes can be designated for detecting the pH of different regions of the digestive tract, including the stomach and intestine, which have different pH ranges. In an application such as an ingestible pill, the pH sensor may have an electrode dedicated to detecting 130412.doc -13· 200914822 present in the low pH of the stomach t, but having an insoluble at the low pH described above. The compound/polymer electrode has just remained intact as the sensor reaches the higher positive region of the intestine. As shown in Figure 2, an exemplary pH sensor having a first pair of electrodes 25, 25 coated with a first compound/polymer 28. The apparatus further includes a second pair of electrodes 29, Μ coated with a second compound/polymer 30. The second compound: the polymer is soluble in a solution, and the rate of solubility may depend on the pH of the solution. I’m on the same sound.
C Ό * $體實施例令,第-化合物/聚合物在C Ό * $ body example, the first compound / polymer in
低於一测值時不可溶解,且第二化合物在低於第二PH 閾值時不可溶解。在另一具體實施例,第—化合物/聚合 物在高於-PH閾值時不可溶解,且第二化合物/聚合物在 低於第二PH閾值時不可溶解。在又另一具體實施例,該第 -化合物/聚合物在低於一阳間值時不可溶解且該第二 化合物/聚合物在低於第二P關值時不可溶解。 如圖2所示’將電極暴露於一試樣溶液27中,且藉由以 恒定時間間隔施加-交流電壓18至電極而監測各對;極之 間的阻抗或電導。使用至少兩個連續測定值的阻抗值以計 算電導變^速1。所計算出的電導變化速率與儲存的資料 ===前的PH值極限或試樣溶液的實際阳值。根 據本揭不内谷’該PH感測器可具有—對以上以具有剛 值介於2與6.5的化合物/聚合物塗布的電極, 可與任何其他電極對的pH閾值*同。請注意電極 圖2所示的平板,根據f要可 二盘如 * ,,.. 尺刊的形狀與佈 。’所有電極無須在所圖2所示的分離的載體上製 130412.doc -14- 200914822 造’可在相同物理載體上製造。一系統時鐘(此處未顯示) 可用於使資料流與處理同步。 參考圖3 ’ pH感測裝置包括第二化合物/聚合物38,其包 覆塗布該電極對39、39,的第一化合物/聚合物36。第二化 s物/1 〇物可用於保護第一化合物/聚合物在第二化合物 聚合物溶解之前免於被溶解。該組合可設計以容許檢測在 消化道中需要通過一具有類似pH的較早區域之區域的 PH。在一具體實施例中,該第一化合物/聚合物刊在低於 —PH閣值時不可溶解,且第二化合物/聚合物“在低於第 二pH閾值時不可溶解。在另一個具體實施例中,該第一化 合物/聚合物36在高於一pH閾值時不可溶解,且第二化合 物/聚合物38在低於第二值時不可溶解。在又另一具 體實施例中’該第-化合物/聚合物36在高於—ρ關值時 不可溶解,且第二化合物/聚合物38在高於第二pH閣值時 不可令解。在又再另一個具體實施例巾,該第一化合物, 聚合物36在低於一劑值時不可溶解,且第二化合物/聚 合物38在高於第二ρΗ閾值時不可溶解。 該ΡΗ感測器可包括至少一 ^ 对電極,其以具有限定pH閾 值的較厚的第一化合物/聚合物 人初興具有一不同於該第一化 合物/聚合物之pH閾值的較薄 的第一化合物/聚合物予以塗 布。在此組態中,保護第—化人 M ^ 〇物/1合物免受不預期的 暴路。例如’製造一 ρΗ感測 當的化合物/聚合物係在ΡΗ值高於j:腸中的ΡΗ,一適 聚合物。然而,可攝取的藥丸4 "不溶解之化合物/ v式之ΡΗ感測器被患者吞服 130412.doc -15 - 200914822 之刖及之後不久,該感測器可能有機會暴露至pH高於6之 液體中。為了保護感測器免受不預期的或過早的暴露,可 使用在pH低於5之前不溶解的化合物/聚合物作為具有pH閾 值6的化合物/聚合物上的一薄塗層。該薄的頂塗層在胃的 低pH環境中快速溶解,且結腸pH感测器將為部署做好準 備。該薄塗層之經感測的溶解可能過快而不能提供精確的 pH值,但可用作一PH感測器藥丸通過的陸標。Not soluble below a measured value, and the second compound is insoluble below the second pH threshold. In another embodiment, the first compound/polymer is insoluble above the -PH threshold and the second compound/polymer is insoluble below the second pH threshold. In yet another embodiment, the first compound/polymer is insoluble at less than a positive inter-value and the second compound/polymer is insoluble below a second P-off value. The electrodes are exposed to a sample solution 27 as shown in Figure 2, and each pair is monitored by applying an -AC voltage 18 to the electrodes at constant time intervals; the impedance or conductance between the electrodes. The impedance value of at least two consecutive measured values is used to calculate the conductance variable speed 1. The calculated rate of change of conductance is the limit of the pH before storage === or the actual positive value of the sample solution. According to the present disclosure, the pH sensor can have the same electrode pH as above for any other electrode pair coated with a compound/polymer coated with a polymer having a value between 2 and 6.5. Please pay attention to the electrode shown in Figure 2. According to f, you can use two plates, such as *, ,.. 'All electrodes need not be made on the separate carrier shown in Figure 2, 130412.doc -14- 200914822 can be made on the same physical carrier. A system clock (not shown here) can be used to synchronize the data stream with the processing. Referring to Figure 3, the pH sensing device includes a second compound/polymer 38 that coats the first compound/polymer 36 of the electrode pair 39, 39. The second s/1 sputum can be used to protect the first compound/polymer from being dissolved prior to dissolution of the second compound polymer. This combination can be designed to allow detection of the PH in the digestive tract that needs to pass through an area of an earlier region having a similar pH. In a specific embodiment, the first compound/polymer is insoluble at a pH below -PH, and the second compound/polymer is "not soluble at a lower than the second pH threshold. In another implementation In one example, the first compound/polymer 36 is insoluble above a pH threshold and the second compound/polymer 38 is insoluble below a second value. In yet another embodiment, the - compound/polymer 36 is insoluble at temperatures above -ρ, and second compound/polymer 38 is not resolved above the second pH. In yet another embodiment, the A compound, polymer 36 is insoluble at less than a dose of the agent, and the second compound/polymer 38 is insoluble at a temperature above the second pH threshold. The germanium sensor can include at least one pair of electrodes, A thicker first compound/polymer having a defined pH threshold is initially coated with a thinner first compound/polymer that is different from the pH threshold of the first compound/polymer. In this configuration, Protecting the human-M ^ 〇 / / 1 compound from unexpected The violent path. For example, 'manufacturing a compound/polymer system when the enthalpy is higher than j: ΡΗ in the intestine, a suitable polymer. However, ingestible pills 4 " insoluble compounds / v The sensor is swallowed by the patient 130412.doc -15 - 200914822 and shortly thereafter, the sensor may have exposure to a liquid with a pH above 6. In order to protect the sensor from unintended Or premature exposure, a compound/polymer that does not dissolve before pH below 5 can be used as a thin coating on the compound/polymer with a pH threshold of 6. The thin topcoat is in the low pH environment of the stomach. Quickly dissolves, and the colon pH sensor will be ready for deployment. The sensed dissolution of the thin coating may be too fast to provide an accurate pH value, but can be used as a PH sensor to pass the pill Landmark.
現參考圖4,所揭示的pH感測裝置可包括一介於電極42 與化合物/聚合物塗層48之保護層46。如圖4所示,示範性 的電極42安裝在一基板44上,並在其由化合物/聚合物48 覆蓋前用一保護層46底塗。該保護層可由一適合的物質形 成’例如,鉻、金、鉑、金屬氧化物或聚胺醋。該保護層 係用於保護電極在試樣溶液(諸如胃腸液)中免受腐蝕。 參考圖5 ’顯示電極陣列5〇之橫截面。該電極對陣列係 單-PH感測裝置的一部分。如所示,陣列%包括六對電 極’各對具有-用不同於另一包覆電極的化合物/聚合物 所塗布的電極。雖然據圖示僅__對電極52連接到—電路 54,但陣列中的各電極係、連接至電路,該電路包括一電 源、-開關機構與附屬的用於測定阻抗變化率的組件。 該感測器陣列50可包括若干對電極。各電極對可用 解速率在-流體(諸如H+、Na+、酶、葡萄糖、蛋白質/、 病毒、細菌、胺基酿、+ # 或/、他的因素)中以物質濃度作為 =變化的化合物/聚合物予以塗布。因此,可 用於檢測PH以及試樣溶液中其他組份之存在與濃度。在一 130412.doc 200914822 具體實施例中’用對不同物質及/或不同濃度範圍作出反 應的不同化合物/聚合物塗布至少兩對電極。該柵井結構 可便於填充聚合物,且各個井的深度可根據感測器的所需 操作時間進行調整。 Ο 該PH可藉由知道在-既定溶液中已知溶解度的迷率進行 測定。所^的pH感測裝置容許將溶解度速率作為流體傳 導率之時間導數進行収。因|此塗層化合物/聚合物具 有與溶液不同的電導率,隨著化合物/聚合物溶解,液體 填充電極之間的空隙並引起電導率增大。電導率變化可近 似地透過以下適用於分析物濃度高於?11閾值時的情況之等 式與聚合物之溶解度速率關聯。 等式1Referring now to Figure 4, the disclosed pH sensing device can include a protective layer 46 interposed between electrode 42 and compound/polymer coating 48. As shown in Figure 4, an exemplary electrode 42 is mounted on a substrate 44 and primed with a protective layer 46 before it is covered by the compound/polymer 48. The protective layer may be formed of a suitable material such as chromium, gold, platinum, metal oxide or polyurethane. The protective layer is used to protect the electrode from corrosion in a sample solution such as a gastrointestinal fluid. Referring to Figure 5', a cross section of the electrode array 5A is shown. The array of electrode pairs is part of a single-PH sensing device. As shown, the array % comprises six pairs of electrodes' each pair having an electrode coated with a compound/polymer different from the other coated electrode. Although only the __to-electrode 52 is coupled to the circuit 54, the electrodes are connected to the circuit, the circuit includes a power source, a switching mechanism, and an associated component for determining the rate of change of impedance. The sensor array 50 can include a number of pairs of electrodes. Each electrode pair can be decomposed in a -fluid (such as H+, Na+, enzyme, glucose, protein/, virus, bacteria, amine based, + # or /, his factors) with substance concentration as a change compound / polymerization The material is coated. Therefore, it can be used to detect the presence and concentration of PH and other components in the sample solution. In a specific embodiment, at least two pairs of electrodes are coated with different compounds/polymers that react to different materials and/or different concentration ranges. The grid structure facilitates filling of the polymer and the depth of each well can be adjusted based on the desired operating time of the sensor. Ο The pH can be determined by knowing the probability of known solubility in a given solution. The pH sensing device allows the rate of solubility to be taken as the time derivative of the fluid conductivity. Since this coating compound/polymer has a different conductivity than the solution, as the compound/polymer dissolves, the liquid fills the gap between the electrodes and causes an increase in electrical conductivity. The conductivity change can be similarly applied to the following analyte concentrations? The equation for the 11 threshold is associated with the solubility rate of the polymer. Equation 1
% in ^electrodesPfluid (^*>Q dYp{r,t^% in ^electrodesPfluid (^*>Q dYp{r,t^
Z dtZ dt
+ Q 'hreshold+ Q 'hreshold
在等式1中,c係所測的溶解度速率,其中%係比例係 數,尤如係電極之間的距離,P//—係溶液的電阻率, 係在pH閾值時溶解度速率,且γ係電極之間的電 導率。 亦提供一種用於檢測一溶液中pH之系統。該系統包括一 化合物/聚合物塗布的電極及測定在一溶液在電極處之電 導之構件。用於測定的構件包括任何適當的電子系統,包 括用於測定電導變化速率的電路,其在此項技術中係已 知。在所揭示的系統中,化合物/聚合物係可溶於溶液 130412.doc -17- 200914822 中,且溶解度速率可取決於該溶液的pH。 =提供_種敎—㈣之pH之方法。該方法包括提供一 :化合物/聚合物中或由一化合物/聚合物塗布的電極。 物/聚合物具有pH相關的溶解度分佈。此帅關之 ☆解度》佈可為此項技術中已知,或其可憑經驗測定。該 I法進-步包括將化合物/聚合物塗布的電極暴露於溶液 — 並測定電極處的電導作為一時間函數。測定了電導 率’ 1藉由使電導率與化合物/聚合物溶解度相關聯來測 () 定溶液的pH。 本揭示提供一種製造方法及/或技術用以小型、低成 f生物相谷、無須校準且足夠可靠的pH感測器以在通過 胃腸道時監測pH。此外,所揭示的pH感測器可用作一拋 棄式感測器以監測在其他環境中的連續pH變化例如在Μ 小時内。基於相同理論,可在各種環境中製造並實施一種 可感測多種物質及/或性質之感測器陣列。 一種包括多個電極之裝置之實例如圖6八及6B所示。此 G pH感測裝置含有分散於三個堆疊層之間的多個電極陣列。 一以此方式組態之裝置經訂定尺寸以便容許裝置可被攝取 並可提供用於其他離子與生物因素之?11資訊與濃度資訊。 實例 實例1 :使用聚合物包覆的電極來測定 測定一浸於一試樣液體中的電極之阻抗。使用—用 EUDRAGIT聚合物L30-D55或E100塗布的指叉型電極陣 列。使用了三個試樣溶液。兩種溶液係鹽含量為〇·2%至 0 · 6 /〇 w/v及pH為5.7之鹽水。使用鹽酸調整pH,且用一 130412.doc 200914822In Equation 1, c is the measured solubility rate, where % is the proportional coefficient, such as the distance between the electrodes, the resistivity of the P//- solution, the solubility rate at the pH threshold, and the γ system. Conductivity between the electrodes. A system for detecting the pH in a solution is also provided. The system includes a compound/polymer coated electrode and means for determining the conductance of a solution at the electrode. The means for determining includes any suitable electronic system, including circuitry for determining the rate of change of conductance, as is known in the art. In the disclosed system, the compound/polymer is soluble in solution 130412.doc -17- 200914822 and the rate of solubility may depend on the pH of the solution. = Method of providing the pH of the seedlings - (iv). The method comprises providing one: an electrode in a compound/polymer or coated with a compound/polymer. The material/polymer has a pH dependent solubility profile. This handsome ☆ solution can be known in the art or it can be determined empirically. The I step involves exposing the compound/polymer coated electrode to a solution - and determining the conductance at the electrode as a function of time. The conductivity '1' was determined by determining the pH of the solution by correlating the conductivity with the compound/polymer solubility. The present disclosure provides a manufacturing method and/or technique for pH sensors that are small, low-definition, non-calibrated, and sufficiently reliable to monitor pH as they pass through the gastrointestinal tract. In addition, the disclosed pH sensor can be used as a disposable sensor to monitor continuous pH changes in other environments, such as within hours. Based on the same theory, a sensor array that senses multiple substances and/or properties can be fabricated and implemented in a variety of environments. An example of a device comprising a plurality of electrodes is shown in Figures 6 and 6B. The G pH sensing device contains a plurality of electrode arrays dispersed between three stacked layers. A device configured in this manner is sized to allow the device to be ingested and available for other ionic and biological factors? 11 information and concentration information. EXAMPLES Example 1: Determination of the impedance of an electrode immersed in a sample of liquid using a polymer coated electrode. Use—An array of interdigitated electrodes coated with EUDRAGIT polymer L30-D55 or E100. Three sample solutions were used. The two solutions are brines having a salt content of 〇·2% to 0·6 /〇 w/v and a pH of 5.7. Adjust the pH with hydrochloric acid and use a 130412.doc 200914822
Corning(玻璃電極)pH計CHEKMITE PH-15校準試樣pH。 使用不3蛋白貝的模擬胃液(SGF)(Ricca Chemical Part# 7108-32),其為 pH 為 l.i 的 〇.7〇/。v/v HC1 中的 0.2% w/vCorning (glass electrode) pH meter CHEKMITE PH-15 calibrates the pH of the sample. A simulated gastric juice (SGF) of not 3 protein shells (Ricca Chemical Part # 7108-32) was used, which was 〇.7〇/ at a pH of l.i. 0.2% w/v in v/v HC1
NaCl。亦使用模擬腸液(SIF)uspxxn(Ricca chemicalNaCl. Simulated intestinal fluid (SIF) uspxxn (Ricca chemical)
Part# 7109.75-16),其係〇·68%鱗酸一鉀與氫氧化鈉。最終 溶液係pH 7.4。 將二個以相同的在pH高於5 5之前不溶解的聚合物L3〇_ D55塗布的電極分別浸於三個試樣溶液中。由於聚合物溶 ( 解使電極之間的電導隨時間變化。在不同pH值的流體中電 導變化速率分化良好。對於電容為_3 3毫微法拉(nf)、pH 為7.4的溶液,作為電阻之倒數以微西門子(ms)報告的阻抗 迅速上升至63 ms。pH 5.7溶液阻抗變化不那麼大,僅達到 36 ms與電容-0.6 nf,且pH K1的溶液之阻抗變化不大為48 ms與-9.1電容。 將用相同的聚合物L30-D55塗布的相同電極連續地浸於 I》 T同PH值的流體中。儘管歷程接觸不同pH值的溶液,依 存於pH的電導變化速率保持一致。 進打了另外的實驗以確認〇 2%至1%的鹽含量並不影響 聚合物之反應。已證實其他聚合物之類似再現性,包括^ 液低於pH 5之前不溶解之聚合物。 根據本揭示内奋’可使用具有其他pH閾值的額外化合物 及/或聚合物。因此,藉由使用多對以不同_值之化合 物/聚合物塗布的電極,可以俗植_ J以所揭不的pH感測器監測大範 圍的pH。同樣地,可測定妹之八p 1 θ 列疋卉多分析物含量,如此處所述。 130412.doc -19- 200914822 雖然本發明已參老牲 ㈣實施例進行㈣與描述, 本發明非曰在限制所示的細 ^ ^ r m 〇 ^ „ 在申凊專利範圍 均專祀圍内且不背離本發 乃的匱況下可對細節進行各種 P文艮。 【圖式簡單說明】 圖圖1係根據本揭示内容之PH感測器之具體實施例之示意Part# 7109.75-16), which is 〇68% scalar monopotassium and sodium hydroxide. The final solution was pH 7.4. Two electrodes coated with the same polymer L3〇_D55 which were insoluble before pH 5 5 were respectively immersed in three sample solutions. Due to the dissolution of the polymer (the conductivity between the electrodes changes with time. The conductivity change rate is well differentiated in fluids with different pH values. For a solution with a capacitance of _3 3 nanofarads (nf), pH 7.4, as a resistor The reciprocal of the impedance reported by MicroSiemens (ms) rises rapidly to 63 ms. The impedance change of the pH 5.7 solution is not so large, only 36 ms and the capacitance is -0.6 nf, and the impedance of the solution of pH K1 does not change much to 48 ms. - 9.1 Capacitance The same electrode coated with the same polymer L30-D55 was continuously immersed in a fluid having a pH value of I. T. Although the solution was contacted with a solution of different pH values, the rate of conductance change depending on the pH remained the same. Additional experiments were conducted to confirm that the salt content of 〇2% to 1% did not affect the reaction of the polymer. Similar reproducibility of other polymers has been demonstrated, including polymers that are insoluble before the pH is below 5. In the present disclosure, additional compounds and/or polymers having other pH thresholds can be used. Therefore, by using a plurality of pairs of electrodes coated with different values of the compound/polymer, it can be smothered. pH sensor monitoring is large The pH of the range. Similarly, the polyp analyte content of the octave p 1 θ 疋 可 can be determined as described herein. 130412.doc -19- 200914822 Although the present invention has been carried out (iv) and described, The present invention is not limited to the details shown in the drawings. The various details can be applied to the details within the scope of the patent application and without departing from the present invention. Figure 1 is a schematic illustration of a specific embodiment of a pH sensor in accordance with the present disclosure
圖2係根據本揭示内容之pH感測器之另一具體實施例之 示意圖。 具體實施例之 圖3係根據本揭示内容之pH感測器之另一 示意圖。 圖4係根據本揭示内容之塗被電極之實施例之示意圖。 圖5係含有根據本揭示内容之具體實施例之電極陣列的 pH感測器之示意圖。 圖6 A係含有根據本揭示内容之具體實施例之電極陣列的 pH感測器之示意圖。 圖6B係圖6A所示之pH感測器之側視圖。 【主要元件符號說明】 10 試樣溶液 12 電極 12, 電極 14 化合物/聚合物塗層 15 連接 16 電開關 130412.doc -20- 200914822 18 電源 20 連接 22 資料處理器 24 資料記憶體組件 25 電極 25' 電極 26 報告或顯示一 pH值的組件 28 第一化合物/聚合物 29 電極 29' 電極 30 第二化合物/聚合物 36 第一化合物/聚合物 38 第二化合物/聚合物 39 電極 39' 電極 42 電極 44 基板 46 保護層 48 化合物/聚合物塗層 130412.doc -21 -2 is a schematic illustration of another embodiment of a pH sensor in accordance with the present disclosure. DETAILED DESCRIPTION OF THE INVENTION Figure 3 is another schematic illustration of a pH sensor in accordance with the present disclosure. 4 is a schematic illustration of an embodiment of a coated electrode in accordance with the present disclosure. Figure 5 is a schematic illustration of a pH sensor containing an electrode array in accordance with a particular embodiment of the present disclosure. Figure 6A is a schematic illustration of a pH sensor containing an electrode array in accordance with an embodiment of the present disclosure. Figure 6B is a side view of the pH sensor shown in Figure 6A. [Main component symbol description] 10 Sample solution 12 Electrode 12, Electrode 14 Compound/polymer coating 15 Connection 16 Electrical switch 130412.doc -20- 200914822 18 Power supply 20 Connection 22 Data processor 24 Data memory component 25 Electrode 25 'Electrode 26 Reports or displays a pH component 28 First Compound / Polymer 29 Electrode 29' Electrode 30 Second Compound / Polymer 36 First Compound / Polymer 38 Second Compound / Polymer 39 Electrode 39 ' Electrode 42 Electrode 44 Substrate 46 Protective layer 48 Compound/Polymer Coating 130412.doc -21 -
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CN113899801A (en) * | 2014-12-19 | 2022-01-07 | 豪夫迈·罗氏有限公司 | Test element for electrochemically detecting at least one analyte |
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US20080248900A1 (en) | 2007-04-05 | 2008-10-09 | Gus Hernandez | Practice baseball swing machine |
JP2010538292A (en) * | 2007-09-06 | 2010-12-09 | コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ | Method and apparatus for chemical analysis of fluids |
RU2586817C2 (en) * | 2010-11-10 | 2016-06-10 | Конинклейке Филипс Электроникс Н.В. | pH CONTROL DEVICE |
EP3395825B1 (en) * | 2010-12-16 | 2021-11-10 | Takeda Pharmaceutical Company Limited | Real time monitoring and control of protein production processes using impedance spectroscopy |
US20150192540A1 (en) * | 2012-10-18 | 2015-07-09 | Bio Sensor Inc. | Sensor, sensor module, and detection method |
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DK0700520T3 (en) * | 1993-05-29 | 1998-03-02 | Cambridge Life Sciences | Sensors based on polymer conversion |
GB2350677A (en) * | 1999-06-04 | 2000-12-06 | Cambridge Life Sciences | Enzyme detection |
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CN113899801A (en) * | 2014-12-19 | 2022-01-07 | 豪夫迈·罗氏有限公司 | Test element for electrochemically detecting at least one analyte |
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