TW587171B - Biomolecule diagnostic devices and method for producing biomolecule diagnostic devices - Google Patents
Biomolecule diagnostic devices and method for producing biomolecule diagnostic devices Download PDFInfo
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- G03H1/182—Post-exposure processing, e.g. latensification
Description
玖、發明說明: 【發明所屬之技術領域】 本發明爲_-般偵檢培養財的分析物之細,且更特别的是 準備特枝析物診_檢器的伽,以表示在培養基中有分析物,舉例來 説,一繞射/全像術形式。 【先前技術】 有許多系統及設備可利用於偵檢在各種不同培養基上的各種廣 泛分析物β無論贿,許錢前紐及設備解貴,且綱料家執行此 試驗。需認清生物感測系統系統爲容易製造且價位低,並能夠確實且敏銳 偵檢分析物^舉例來説,參考美國專利編號第5,922 55G號、第6,細,256 號及第6,221,579B1號。 在製造生物感測系統的工業中已有各種不同進展。舉例來説, K_r等人㈣國專稿縣切2,^號乃描述包括聚合物酵化物(具有 金屬塗層)的設備。分析物特定接受層蓋印於塗料的電路基板上。當分析物 固定至設備時,輯繞_案。絲親設備(比如分光計)制於測定繞 射圖案的絲。無論诚,絲龍備的缺職事實上繞侧餘法被肉 眼辨别’目此合成_現設備f檢視繞射时^並且,此設備—般無法偵 檢較小的分析物,此無法產生顯著的繞射圖案。
Bogart等人的美國專利編號第5,482,83〇號描述包括具有旋光表 面的酵化物之設備,此顯示反應光碰撞的第一個色彩。此第一個色彩定義 爲放射光的光譜分布。酵化物也顯示與第_個色彩不_第二個色彩。第 二個色衫顯π分析物在表面上時所反應的蝴光線。_色彩至另一個的變 化不是使贱器就是用肉眼囉。無論如何,設備的賴爲設備的費用較 南,以及控制晶片酵化物上之各種不同層的問題。 接觸印片拷貝技術已探測產生具有自動裝配的單層。美國專利編
Mavis-C:\WINSOFT\ 專和JVPkOO 1 ·08〜\0843\ΡΚ-001 -0843.doc2003/8/21 587171 號第5,922,550號描述具有金屬化薄膜的生物感測系統,此爲印刷(接觸印 片拷貝)一特定估計圖案的特有分析接受器。接受器材料固定至自動裝配單 層’並爲特有分析物或—齡析物。選定的分析物可將分縣附著至金 屬化塑膠雜的鱗_,藉由物狀寸及細紐置,接受器印刷引起 牙透光與/或者反射光發生繞射。以眼睛或任意以_設備輕騎見產生的 繞射影像。美國專號第⑽,256號描述具有金屬化義_似設備, 此根據印刷-特有估相細特有分析物接受器。,Μ6糊並不限定於自 動裝配單層,但指科使職學連結至_表面雜何接受器。,a%專利的 發明使用接觸印片拷H _單層的方法,此乃顧微生物的黏合劑衍生 物。此一衍生物的範例爲硫醇。理想的接合劑可爲硫醇抗體或抗體片、蛋 白質、核酸、糖、碳水化合物或任何其他實用的固定分析物。舉例來説, 衍生物可藉由硫醇而化學黏結至金屬表面(比如金屬化聚合物薄膜)。 對製造以繞射爲根據的生物感測系統而言,描述於上的接觸印片 拷貝技術之潛在發布在印刷作用期間有可能受印刷(即蓋印)的牵制。並 且’由於壓力及接觸變化爲固有的作用(即表面能量變化),有可能不規則 或物質塗油墨。 本發明爲關於可輕易製造及價位低的生物感測系統系統,此能夠 確實敏銳偵檢分析物,且避免有傳統微接觸印片拷貝技術之缺點的可能。 【發明内容】 發明的目的及優點將邵分在下面發表,或可由描述中顯而易見, 或可透過發明實施而學到。 本發明提供較不昂貴且敏感的生物感測系統設備、製造此生物感 測系統設備的方法以及偵檢培養基中感興趣的分析物之方法。 生物感測系統包括含有感光劑的酵化物。感光劑一般可一律運用 於酵化物構件的整個表面上層。或者,酵化物可含有不可缺成分的藥劑。
Mavis-C:\WINSOFT\$ilJ\PkOO 1 ·08~\〇843\ΡΚ-001 -〇843.doc2003/8/21 舉7來説,感光劑可爲光酸(Photo-acid)或光氧化劑。藥劑在溶液中爲“透 明”聚合物’舉例來説有PVC、聚苯乙鱗等,且溶液的賴膜可藉由旋 轉塗佈作用而施用於酵化物構件。在铸的實施财,義可包埋或聚合 於酵化物中。特殊的可雛加強劑可結合_。酵化物可根據置放於特别 刺激物(例如光)而由製造酸性、驗性或氧化劑的材料形成。 酵化物可由各種廣泛適當材料的任何一個,包括塑膠、塗有金屬 的塑膠及破璃、實用性塑膠及玻璃、梦晶片、痛、玻璃等等形成。 感光劑由許多已知技術(包括浸泡、喷灑、滾動、紡紗塗層及任 何其他技術)作爲—層防光職,針此層—般可—律賴於酵化物的 整個試驗表面上方。發明也包括運用感光劑層的接觸印刷方法。 然後同樣在防光環境中,含有接受性材料(例如原生質分子)的層 運用於感細層上方。接受性材料層可運崎多已知技術,包括浸泡、喷 灑、滚動、纺紗塗層及任何其他技術,其中此層一般可一律運用於酵化物 的整個試驗表面上方。發明也包括運用接受性材料層的接觸印刷方法,此 方法在一方式中處理,以在塗佈作用期間防止不調和的墨汁及污染以免接 觸。 然後接受性材料層定義爲藉由將遮罩置放於酵化物上方之接受 性材料之活化及未活化的圖案,且之後以能源照射酵化物,此足以促進遮 罩露出或未保護地區中的感光劑反應。感光劑的活化作用結果在露出地區 中使過原生質分子變性。因此,接受性材料在無法更長與共軛配合基(包括 感興趣的分析物)連結下爲“無效"(deactivated)。 遮罩可包括庇護或保護地區及露出地區(例如空白、透明或半透 明地區以及遮罩結構中的孔或開口)的任何理想圖案。遮罩的露出地區定義 爲接受性材料的未活化地區之圖案,且遮罩的保護地區定義爲活化接受性 材料地區的圖案。因此,遮罩提供保護感受性材料地區,並提供置放於至
Mavis-C:\WINSOFT\ 專利\Pk001.08〜\0843\PK-001-0843.doc2003/8/21 587171 少在照射能源附近地區,以活化下面的感光劑。 將了解發明並不限定於遮罩的任何特殊圖案。實際上可能爲許多 及結合露她區_口。在-翻實酬中,时鱗化物之嫌表面上 每間隔約5微米有約10微米直徑的圖素。 感光劑及接受性材料層尤其選擇以能源照射,以活化感光劑的特 定類型。發猶制於任何特定聽,彳來説,能财爲光源,例如 紫外線光源、電子束、放射能源等等。 根據隨後生物感測系統露至含有感興趣分析物的培養基中,分析
物連結至活魏區㈣接受性撕。織生物_紐雜無化地區一 致的繞射时中繞射穿透光。繞射圖案可關眼看出,或任意以感測設備 看出。 在分析物沒有散播可見光的情形,因爲與周圍培養基比較下,分 析物太小,或不具有可察覺的折射率差異,可使祕高繞射的構件,比如 聚口物微77子。這些微分子可塗上黏合劑或也可明確連結至分析物的接受 性材料。«舰分析物連接至接受性概層微微分子中的二個製成的 原生質分子’繞射影像可輕易由眼喊任意轉測設備看出。
<皆由“繞射”(diffracti〇n)意謂當波由妨害展開越過物體幾何影 像限制的阻礙時之财。當物體尺寸與波的波仙同,記雜果。在本發 明中’阻錄爲分聽(有或沒有絲加微分子),且波爲光波。 在本發明的另一實施例中,將特有種類的微生物之營養物併入接 受性材料層。在此方式巾,非常低濃度的微生物可由第—次接觸本發明並 熱營養物的生物細系統’織在適合於連結微生物生長的情況下培養生 物感測系統。允許微生物生長直到有足夠的微生物軸繞射圖案。 本發明提供可大量生產之低價、可棄式的生物感測系統。本發明 的生Uj系統可由單次試驗偵檢分析物,或可由多個試驗設備構成。本
Mavis-CAWINSOFR 專和JVPlcOO 1 ·08〜\0843\ΡΚ-001 -0843. doc2003/8/21 587171 發明使用的生物感測系、统包括(但不受限)衣物(比如尿布)中的化學或生物 污染的偵檢’在出售前包裝食_如果収其域新婦^污雜 檢’以及在健康賴用途(比如診斷荷爾蒙、蛋白質、抗原、核酸、微生物 及血液成分的侦檢裝備)中使用本發明的生物感測系統。需了解本發明並不 限定任何使用或用途。 本發明的這些及其他特性將在下面詳述揭發實施例觀察後變得 顯而易見。 【實施方式】 目前發明將參照特有實施例做更詳細的描述。這些實施例經由發 明解釋提供實施例’並不意謂對發明有所限制。舉例來説,可使用另一實 施例描述或制部分實施_特性,域生進—步實補。在發明的範圍 及精神内’本發明意圖包括這些及其他變更及變動。 本發明描寫改善生物感測設備的特徵,以及使用此生物感測設備 以债檢及浙感驗分析録培養基内存錢數量的方法。可由本發明偵 檢的分析物包括(但不受限)微生物,比如細菌、眞菌及病毒。根據發明的 生物感測設備較不昂貴,且具有傳錄接觸印刷生祕_統的優點。 在一般用語中,本發明包含一作用,此作用定義爲在酵化物表面 上由光罩(photo-masking)此酵化物的特有分析物接受器材料之活化圖案。 舉例來説,感光劑藉由含有藥劑的紡紗塗層與酵化物構件結合,形成酵化 物構件。或者,藥劑可包埋或聚合於酵化物中。在另一實施例中,酵化物 可在部份或整個感光物質㈣成。舉例來説,根據置放於…光,酵化物 可爲PVC(聚氣化婦),此將產生HCl(鹽酸)。根據放置於uv光下,多胺 將產生鹼性。然後將一般接受性材料的相同塗層運用於感光劑上方的酵化 物表面。遮罩置放於酵化物上方,且以能源照射遮罩及酵化物,以明確選 擇活化感光劑。在本身鹼性中,“遮罩”作爲保護酵化物構件的至少一地
Mavis-C:\WINSOFT\i^lJ\Pk001.08~\0843\PK-001-0843.doc2003/8/21 區或部分以免照射能源,並適合將至少一鄰接部分暴露於能源。舉例來 説’遮罩一般可爲具有保護區域印有任何圖案的透明或半透明空白(例如材 料片)。遮罩露出的爲保護區域相當於酵化物構件的露出地區。或者,遮罩 可簡單爲置放於酵化物上的單一物體。保護物體下方的地區,因此定義爲 接受性材料的活化地區,且物體四周地區暴露於能源,且因此定義爲未活 化接受性材料的地區。或者,物體可具有相當於露出地區的開口圖案。 如上提及,選擇能源使露出的感光劑活化,因此使過原生質分子 變性。換句話説,活化的感光劑可爲任一許多物質,比如二芳基碘鹽 (diaryliodonium salts)、三芳基硫鹽(triarylsulfonium salts)、二含氮磺酸鹽 (diazosulfonate)、含溴雙酚 A(br〇mobisphenol A)、某含氣聚合物(certain
Cl_containingpolymei:)、酸性或鹼性生產聚合物、二垸基苯(甲)醯甲基硫鹽 (dialkylphenacylsolfonium salts)等等或光氧化劑(比如 Ζη〇、ή〇2)以及某銅 與釕的合成物。在一特别實施例中,藥劑爲光酸,比如Triphenylsolfonium inflate - (4-iodophenyl) diphenylsulfonium inflate ' Diphenyliodonium p-toluenesulfonate ^ Bis(4-t-butylphenyl) iodonium p-tolulenesulfonate ^
Bis(4-t-butylphenyl) iodonium triflate 以及 Tris(4-t_butylphenyl) sulfonium triflate。在另一實施例中,藥劑可爲光氧化劑,比如在硝基氣甲苯 (nitrobenzylbromide)中的 ZnO、Ti02、Cu[2,9-二苯基-1-10-雜菲]2+;以及 Co[(NH3)5C1]2+中的Ru[2,2'-二坤t。定]32+。在由遮罩保護之區域中的感光劑剩 下未活化。因此,;f艮據除去遮罩,活化及未活化材料地區的圖案由酵化物 構件定義。將了解“圖案"(pattern)包括同活化地區及未活化地區一樣少。 根據隨後生物感測系統暴露於含有感興趣分析物的培養基,此分 析物將連結至活化地區中的原生質分子。分析物結果爲可見繞射圖案中的 穿透光與/或者反射光的繞射相當於活化地區。如更詳細探討於下,增強器 可使用於提高極小分析物的繞射。
Mavis-CAWINSOFn^jpiJVPkooi ,08-\0843\PK-001 -0843.doc2003/8/21 j Q 587171 考慮使用本發明偵檢的這些分析物包括(但不限定)細菌;酵母菌; 眞菌;病毒;風濕性因素;抗體(包括IgG、IgM、IgA、IgD以及IgE抗體);癌 胚抗原;鏈球菌群A抗原;病毒抗原;與自體免疫疾病、過敏原、腫瘤抗原有 關的抗原;鏈球菌群B抗原、HIVI或HIV II抗原;或對這些及其他病毒的 宿主感應(抗體);特定對RSV的抗原或對病毒的宿主感應(抗體);抗原;酵素; 荷爾蒙;多醣類;蛋白質;油脂;碳水化合物;藥品或核酸;沙門氏桿菌;念珠屬菌 種類(包括(但不限定)綠色菌落以及Candida tropicalis);奈瑟氏球菌屬組A、 B、C、Y及Wsub 135、鏈球菌群肺炎、大腸桿菌、嗜血桿菌屬流行性感 冒類型A/B;衍生自微生物的抗原;PSA(前列腺特異抗原)及CRP(C-反應蛋 白質)抗原;半抗原;濫用藥品;治療性藥品;環境藥劑;以及肝炎的特有抗原。 如此處所使用“感興趣的分析物”(analyte 〇f interest)爲認爲自生物樣本存在 或不存在的任何藥劑表示特殊健康狀態或情形。 也考慮可將特定種類的微生物之營養物併入接受性材料層。在此 方式中,可用本發明的生物感測系統與併入的營養物至可疑的培養基而偵 檢出微生物的極低濃度,然後在適當連結微生物生長情況下培養生物感測 系統。允許微生物生長直到有足夠的有機體形成一繞射圖案。當然,在一 些情形中,存有微生物,或可增加足_成—繞射_,此絲化接受性 材料地區中不需有營養物。 接受性材料由明確能夠將感興趣的分析物連結爲其特徵。可使用 作爲接受性材料的各種材料僅由選擇性(關於任何選擇的樣本)與第二搭檔 結合的材料類型關。接受性材料騎有種類之材料次贿包括毒素、抗 體、抗體彳段、抗原、荷爾蒙接受器、寄生蟲、細胞、半抗原、代謝物、 過敏原、核酸、核子材料、自身抗體、血液蛋白f、細胞片、酵素、組織 蛋白質、酵素酵化物、輔梅、神經傳遞物質、病毒、病毒顆粒、微生物、 蛋白質、多糖類、螯合劑、藥品、適合體、縮氨酸以及特定連結對的任何 11 讓2 丨 587171 其他構件。此制出結合-些可塗至酵化物表面上的許多不啊料, 與感興趣的分析物連結 生薄的薄賴驗系統。不論選擇祕趣的分析物,接受性材料設計成明確
含有感興趣分析物的基質或培養基可爲液體、固體或氣體,並可 包括體離如絲織、輕、驗、歧、_、魏、大齡骨流體、 血漿、淋巴液、所有血液、唾液、缓和溶液、抽取溶液、精液、陰道二 物、心包膜、胃、麵、繼或無親鱗等)。祕趣的精物可爲抗 原、抗體、酵素、DNA片段、未觸動基因、抓八片段、小分子、金屬、 毒素、環_、_、雜漿成分、毛髮或鞭毛成分、蛋白質、多糖類、 藥品或任何其他材料。舉例來説,靖的接受性材料可明確連接一表面薄 膜成分、蛋白質或油脂、多糖類、核酸或酵素。_特有的分析物可爲多 糖類、酵素、核酸、賴成分或祕_而由宿主產生的抗體。分析物的 存在或不存在可表示-傳雜赫(細菌域毒)、腫魏其他代謝失調或 情形。分析物的存在或不存在可表示食物中毒或其他中毒顯心分析物可 表示藥品溢用或可監視治療藥劑的程度。
所利用的科技中,大部分-般遇到的其中一試驗方式爲免疫分 析。無論如何,一般考慮運用於核酸、酵素/酵化物及其他配合基/接受器 試驗方式。對免疫分析而言,抗體可作爲接受性材料,或可爲感興趣的分 析物。接受性材料(舉例來説有抗H或抗原)必須在試驗表面的酵化物表面 上形成-安定較_的反應層。假使魏-抗原,且抗體爲接受性材料, 抗體必須爲特有的感興趣抗原;且抗體(接受性材料)必須以能夠足夠將抗原 保持在試驗表面來連結抗原(分析物)。在一些情形中,分析物不能簡單地 連結接受性材料,但可引起接受性材料發生可察覺的變化。此交互作用可 引起在滅驗表面上質量增加’或在試驗表面上減少接受性材料的數量。後 面的範例爲退化酵素或材料與特定、固定的酵化物交互作用。在此情形中
Mavis-CAWINSom專·咖 〇8〜\_讀 12 -0843.doc2003/8/21 在與感興趣的分析物交互作用之前,一個可看見繞射圖案,但假使飛西物 存在的話則繞射圖案消失。透過分析物與接受性材料發生連結、雜敎或交 互作用的特賴it秋發·不重要,但戰麟最麟驗献t的反應 情形有影響。 除了產生簡單的繞射圖案外,分析物的圖案可允許在可見光中有 全像感應影像與/或者變化的影像。因此,在目前全像中的全像或變化之外 觀將表示正献應。由紐光的前產生賴討爲贿雜,包括(但不 受限)根據分析物連結至接受性材料而由一圖案至另一個的轉化。尤其在較 佳實施例中,在分析物與本發_生物_系統接觸之後,在丨小時内變 得可辨别ά繞射@案。根據與分析物交互_,產錢射光的繞射光栅具 有約1/2波長的最小周期,並具有與四周培養基不_折辨。非常小的 分析物(比如病毒或分子)可間接使用較大的“繞射增進構件”(diffracti〇n enhancing element)(比如微顆粒,即特定的小分析物)來偵檢出。可偵檢的 小刀析物之實施例包含以接受性材料(比如抗體)塗增進顆粒(比如乳膠粒 子或聚苯乙烯粒子),尤其連結至感躺的分析物。可使麟本發明的顆粒 包括(但不受限)玻璃、纖維素、合成聚合物或塑膠、乳膠、聚苯乙婦、聚 碳酸鹽、蛋白質、細菌或黴菌細胞、氧化石夕、醋酸纖維素、碳等等。這些 顆粒理想下爲球狀,但顆粒的結構及空間外形對本發明並不重要。例如, 顆I可爲長條狀、橢圓形、立方體、任意形狀等等。理想顆粒的直徑尺寸 範圍大約爲0.1微米〜50微米,理想大約介於〇1微米及2〇微米之間。顆 粒的組成對本發明並不重要。 理想的是,在酵化物上的接受性材料層尤其將連結至分析物上的 抗原決定位(epitope) ’此與使用於連結至增進顆粒的抗原決定位不同。因 此,對偵檢培養基中的小分析物(比如病毒顆粒)而言,培養基首次置身於 具有特/i接受性材料的乳膠顆粒。培養基中感興趣的小分析物將連結至乳
Mavis-CAWINSOFR 專旱IJ\Pk001.08〜\0843\PiC-0〇l-〇843.doc2003/8/21 13 587171 膠顆粒。然後’任意清洗乳膠顆粒,並置於具有活化接受性材料區域(含有 特定病毒抗體)的生物感測系統。然後抗體連結至乳膠粒子上的病毒顆粒, 藉以將乳膠粒子固定於與薄膜上活化地區相同的圖案。因爲連結的乳膠粒 子將引起可見光繞射,形成繞射圖案,此表示在液體中有病毒顆粒。描述 使用繞射增進顆粒的其他組成,舉例來説有美國專利編號第號, 其合併於此作爲參考。 各種廣泛材料的任何一個可作爲酵化物,以運用接受性材料。此 類材料爲精通技藝人士所熟知的技藝。舉例來説,酵化物可形成許多適當 塑膠、金屬塗佈塑膠及玻璃、實用性塑膠及玻璃、矽晶片、箔、玻璃、酸 性或鹼性的製成的聚合物等等的任何其中一個。將了解假使感光劑爲光 酸,酵化物並非爲金屬或塗上金屬。已發現熱塑性薄膜相當適合。此類薄 膜包括(但不受限)聚合物,比如:聚乙烯_對苯二甲酸酯(MYLAR⑧)、丙烯 腈-丁二烯-苯乙烯、丙烯腈_乙酸甲酯共聚物、玻璃紙、纖維素聚合物(比如 乙基纖維、醋酸纖維素、酪醋酸纖維、丙酸纖維素、鮮爲三醋酸酯、聚乙 烯、聚乙烯-醋酸乙烯酯共聚物、離子化共聚合物(乙烯共聚物)、聚乙烯_ 尼龍共聚物、聚丙烯、甲基戊烯聚合物、聚氟乙烯及芳香聚磺胺)。舉例來 説,其他適當的熱塑性物質及供應者可在參考作業中發現,比如Modem
Plastics Encyclopedia(1923-1996 年紐約的 McGraw-Hill Publishing 公司)。 在發明的一實施例中,其中感光劑爲光氧化劑,熱塑性薄膜可具 有一金屬塗層。有金屬塗層的薄膜可具有大約5%〜95%之間的光學透明 度。使用於本發明的熱塑性薄膜之更理想的光學透明度大約介於2〇%〜80 %之間。在本發明的理想實施例中,熱塑性薄膜至少具有大約8〇%的光學 透明度,且金屬塗層的厚度乃足以維持約大於20%的光學透明度,因此可 由任一反射光或穿透光產生繞射圖案。此表示約2〇 nm的金屬塗層厚度。 無論如何,在發明的一實施例中,金屬厚度大約介於1 nm〜1〇〇〇 nm之間。
Mavis-C:\WINSOFT\ 專利\Pk001 08〜\0843\PK-001-0843.doc2003/8/21 丄 4 587171 沉積於薄膜上的較佳金屬爲金。無論如何,可使用銀、叙、絡、 銅、鐵、錯、白金、鈦及鎳以及這些金屬的氧化物。氧化鉻可使用於製造 金屬化層。 可由任何傳統方法將接受性材料運用於感光層上。運用材料使一 般一定塗在酵化物的整個表面(舉例來説有銅)。可理想運用接受性材料的 非接觸方法,以便藉由接觸印刷設備除去污染的可能性。此非接觸方法包 括(但不受限)浸泡、喷灑、滾動、紡紗塗層及任何其他技術,其中接受性 材料層一般可一律運用於酵化物的整個試驗表面上方。簡單的物理吸附可 發生在許多材料上,比如聚苯乙烯、賴、尼龍或那些精通技藝所熟知的 其他材料。固定特有分析物接受性材料層的特别實施例牵涉分子附著,比 如硫醇或含有二硫化物化合物及金之間的可能性。一般性,含有约5〜2㈨〇 nm厚的金維持在矽晶片、玻璃或聚合物薄膜(比如mylar⑧薄膜)上。在 接受性材料溶液的浸泡或喷灑期間,特有分析物接受性附著至金的表面。 雖然並非最好,發明也包括接觸運用接受性材料的印刷方法。爲 了塗上大量試驗表面及維持接受性材料在施用期間的穩定性及實用性,所 選擇的技術將使所需的接受性材料減至最低。此技術也可將接受性材料運 用或附著至一定及再生方式中的酵化物。 也考慮接受性材料層可在酵化物上形成,作爲金屬化熱塑性薄膜 上的硫醇垸S旨(alkanethiolate)、羧酸、氫氧氨酸及嶙酸的自動組合單層。自 動組合單層有連結的接受性材料。參照文獻爲美國專利編號第5,922,55〇 號,此爲更詳述自動組合單層及製造單層的方法。'55〇專利完全合併於此 作爲參考。 遮罩可由任何適當材料形成,以保護下面酵化物部分免受放射能 源。證實用於定義鍍金mylar®薄膜上的活化及未活化接受性材料區域 之圖案(塗有k體、/谷液)的材料爲具有封鎖或庇護區域印有圖案的透明或半
Mavis-C:\WINSOFT\^^IJ\Pk001.08~\0843\PK-001-0843.doc2003/8/21 15 透明聚合物薄膜(比如MYLAR®)。遮罩類型對具有波長约大於或等於330 nm的光源(照射能源)有益。對具有波長約小於330 rnn的光源而言,可使 用石英或具有鍍鉻封鎖區域的融合矽遮罩。理想中可選擇孔的圖案急尺 寸’以便使活化及未活化區域之間的可見繞射差異達最大。已發現假使活 化區域定義爲一般具有直徑約爲10微米且彼此間距約爲5微米的圓形爲 適當的。 爲了照射遮罩及酵化物組合,可選擇任何適當能源。爲了活化感 光劑的特定類型,尤其選擇能源。舉例來説,能源可爲光源,例如紫外(uv) 光源、電子束、放射源等等。在一特别實施例中,感光劑爲光酸或光氧化 劑(比如個别爲TriphenysulfUlfoniumtriflate或Ti02),且活化能源爲UV光 源。偵檢器置放於光源一段期間,使感光劑充分活化,且因此在露出地區 中的接受性材料成爲未活化。依照感光劑的特别類型,適當波長的光在照 明區域中不是產生酸性、驗性,就是產生氧化劑。這些較大抑止濃度的酸 性、鹼性或氧化劑作爲使接受性材料中的蛋白質變性。“變性,,(denaturing) 不是經由抗體的酸催化、pH誘導構形變化,就是藉由抗體的氧化/基構成, 或結合這些因素。在氣化聚合物的情形中,照射產生抗體,且抑止增加酸 性濃度作爲使抗體變性。將了解發明並不限定於光的類型、活化能源或暴 露的時間。光的類型(例如波長)及暴露的時間可依照感光劑的特有類型而 變化。其他適當能源可包括調整雷射、電子束、各種不同類型的放射光束 (包括7及X放射源)、各種不同強度及光波長(包括在微波及波長以下等等 的足夠大的光束)。需關心的是能源不會破壞(例如融化)下面的酵化物或遮 罩。 第一圖爲根據發明製造生物感測系統之一方法的概要表示。步驟 A表示感光劑作爲層(2)而運用於酵化物構件(4)。步驟B表示接受性材料(原 生質分子)層⑹運用於感光劑層(2)上方的酵化物構件(4)。步驟C表示遮罩
Mavis.C:\WINSOFT\ 專和J\Pk001 _ 08~\0843\ΡΚ-001 -0843. doc2003/8/21 16 587171 (8)沉積在酵化物構件(4)上方。遮罩(8)包括露出或開口區域(10)及封鎖或屁 護區域(12)。步驟D表示遮罩⑻及酵化物構件(4)組合以能源(14)照射。已 知道在遮罩⑻的保護區域(12)下面的酵化物構件⑷被屁護免受能源(η)侵 害。透過遮罩⑻的開口區域(1〇)露出的感光劑(2)由能源(14)促進反應,且 使露出地區的原生質分子變性。保護遮罩(8)的保護地區(12)下面的感光劑 (2)及原生質分子(6),且不要暴露於能源,使得這些區域中的原生質分子(6) 剩下活化。步驟E表示已除去遮罩(8)之後的生物感測系統。生物感測系統 包括接受性材料⑹的活化地區(16)以及無作用地區(18)。活性地區(16)及無 作用地區(18)的圖案相當於遮罩(8)之露出地區(1〇)及保護地區(12)的圖案。 根據發明,生物感測系統具有使用於許多領域的廣大範園。本發 明所使用的生物感測系統包括(但不受限)偵檢衣物(比如尿布)中的化學或 生物污染,此一般在出售前包裝的食物(比如肉類、果汁或其他飲料)中由 微生物來偵檢污染,且在健康診斷用途(比如偵檢蛋白質、荷爾蒙、抗原、 核酸、DNA、微生物及血液構成要素的診斷裝備)中使用本發明的生物感 測系統。本發明也可使用於卿眼鏡、鏡片、窗玻璃、雜玻璃瓶、溶劑 容器、水瓶、急救膠布、擦布等等來偵檢污杂。在一實施例中,本發明考 慮油量計形式,以將示範的酵化物安裝於油量計末端。在使用時,油量計 泡在液體巾,存有涉嫌的分析物,並允許停留數分鐘。織除去油量計, 然後任-光投射經過酵化物,或酵化物由酵化物反射的光觀察。假使觀察 到爲繞射圖案,然後分析物存於液體中。 在本發明的另-實施例中,多數分析試驗在相同支援下構成。長 條可提供數侧案的酵化物部分。每個部分具有不同接受性概,即不同 刀析物了解到本發明可在酵化物上加上各種圖案而成任何列陣構成,以 使用單一試驗偵檢培養基中的多個分析物。 在本發明的又另一實施例中,生物偵測系統可附著至-黏性的背
Mavis-C:\WmSOFAWWk001.08~\0843\PK-001-0843.doc2003/8/21 17 膠·標籤(backed sticker)或移畫印花法(decal),然後此可置放於硬表面或容器 内壁。生物感測系統可置放於容器的内側表面,比如食物包裝紙或玻璃要 水瓶。然後生物感測系統可想像測定是否有細菌污染。 在閲讀此處發明描述之後,將了解發明包括各種不同其他實施 例、變更以及描述於此的發明實施例,顯然那些精通技藝乃無須達背本發 明的範圍及精神。 【圖式簡單說明】 第一圖爲根據發明在遮罩作用中爲了製造生物感測系統之方法 的概要表示。 【圖式元件簡單說明】 2 photo-reactive agent layer 感光劑層 4 substrate member 酵化物構件 6 receptive material layer 接受性材料層 8 mask 遮罩 10 exposed region 露出區域 12 shielded region 保護區域 14 energy source 能源 16 active area 活化地區 18 deactivated area 無作用地區
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Claims (1)
- 拾、申請專利範圍: 1· 一種生物感測系統,其包含·· 一酵化物構件; 一感光劑,此在該酵化物構件的表面; 一接受性材料層,此運用於感光劑,且一般一律塗在該酵化物構 件的側面,該接受性材料爲特定感興趣的分析物; 该層上有該接受性材料的活化及未活化地區的圖案,該活化及未 活化地區由料伽形成,其中在以能雜射鱗錄餅以充分活 化感光劑之前,遮罩置放於酵化物構件上方,使得由該遮罩所露出的 地區足義爲該接受性材料之未活化地區的圖案,且由該遮蔽所保護的 地區定義爲接受性材料之活化地區的圖案;以及 其中當該生物感測系統暴露於含有感興趣分析物的培養基時,分 析物連結至該活化地區中的接受性材料,且之後促進與活化地區一致 的繞射圖案中的穿透光或反射光。 2·如申請專利範圍第1項的生物感測系統,其中該酵化物包含由塑膠、 塗有金屬的塑膠及玻璃、實用性塑膠及玻璃、矽晶片、箔、玻璃及聚 合物薄膜組成的材料表之材料。 3.如申請專利範圍第1項的生物感測系統,其中該感光劑運用作爲該酵 化物構件上的層。 4·如申請專利範圍第1項的生物感測系統,其中該繞射圖案可用肉眼看 見。 5·如申請專利範圍第1項的生物感測系統,其中該接受性衬料以蛋白質 爲基礎。 6·如申請專利範圍第5項的生物感測系統,其中該接受性材料爲_抗體。 7·如申請專利範園第1項的生物感測系統,其中該酵化物構件在足以暴 Mavis-C:\WINSOFT\ 專称PkOO 1. 〇8〜\〇843\ΡΚ-〇〇 1 na 0843 d〇c2003/8/2j 19 8 露經過該遮罩而活化該感光劑的波長下以uv光照射。 如申凊專利範圍第1項的生物感測系統,其中該接受性材料至少爲一 抗原、柷體、核甘酸、螯化物、酵素、細菌、酵母菌、眞菌類、病毒、 έ菌毛髮、含菌鞭毛材料、核酸、多糖類、油脂、蛋白質、碳水化合 物、金屬、荷爾蒙、適合體、縮氨酸及該材料的個别接受器之接受性 材料。 如申凊專利範圍第1項的生物感測系統,其中該感興趣的分析物爲至 +其中一細菌;酵母菌;眞菌;病毒;風濕性因素;IgG、IgM、IgA、IgD以 及1gE抗體;癌胚抗原;鏈球菌群A抗原;病毒抗原;與自體免疫疾病、過 敏原、腫瘤抗原有關的抗原;鏈球菌群B抗原、HIV I或HIV II抗原; 或對這些及其他病毒的宿主感應(抗體);特定對RSV的抗原或對病毒 的宿主感應(抗體);抗原;酵素;荷爾蒙;多_類;蛋白質;油脂;碳水化合物; 藥品或核酸;奈瑟氏球菌屬組A、B、C、Y及Wsub 135、鏈球菌群肺 炎、大腸桿菌、嗜血桿菌屬流行性感冒類型A/B;衍生自微生物的抗 原;PSA(前列腺特異抗原)及CRP(C-反應蛋白質)抗原;半抗原;溢用藥品; 治療性藥品;環境藥劑;以及肝炎的特有抗原。 10·如申請專利範圍第1項的生物感測系統,其中該感光劑爲光酸劑。 11·如申請專利範圍第1項的生物感測系統,其中該感光劑爲光氧化劑。 12. —種製造一生物感測系統的方法,其包含的步驟有: 將感光劑併入酵化物構件的表面; 在感光劑上方形成接受性材料一般一律在酵化物構件的表面上 方,此層含有特定感興趣分析物的接受性材料; 將遮罩置放於酵化物構件上方,遮罩具有一形狀,以便在暴露於 至少一附近地區時可保護酵化物構件的至少一下面地區; 以能源照射酵化物構件及遮罩組合,使足以促進由遮罩露出的地 Mavis-C:\WINSOFT\^ilJ^k001.08~\0843\PK-00l-0843.doc2003/8/21 20 區中之下面接受性材料層的感光劑反應,活化感光劑在未活化的露出 地區中提供接受性材料; 自酵化物構件除去遮罩;以及 其中定義接受性材料的活化及未活化地區之最後圖案,未活化地 區相當於遮罩露出的地區,且活化地區相當於被遮罩保護的地區,因 此當生物感測系統暴露於含有感興趣的分析物時,分析物連結至活化 地區中的接受性材料,並之後在與活化地區一致的繞射圖案中促進穿 透光或反射光發生繞射。 13 •如申請專利範園第I2項的方法,其包含自由塑膠、包覆塑膠及玻璃的 金屬、實用性塑膠及玻璃、矽晶片、玻璃及箔組成的材料選擇酵化物 構件。 4·如申凊專利範圍第12項的方法,其中感光劑爲光氧化劑,且酵化物構 件包含覆有金屬的聚合物薄膜。 5.如申凊專利範園第M項的方法,其中聚合物薄膜包含聚乙烯對苯二 甲酸酯。 16.如申凊專利範圍第丨2項的方法,其包含以肉眼觀看接受性材料之活化 地區的繞射圖案。 17·如申請專利範圍第12項的方法,其中接受性材料以蛋白質爲基礎。 18·如申請專利範圍第17項的方法,其中接受性材料爲-抗體。 19·如申明專利範圍第I2項的方法,其包含以…光在透過遮罩而足以活 化感光劑的波長來照射酵化物構件。 2〇·如申請專利範圍第Π項的方法,其包含自至少其中一抗原、抗體、核 甘酸、螯化物、酵素、細菌、酵母菌、眞菌類、病毒、含菌毛髮、含 菌^毛材料、彳磁、錄類、觸、蛋白質、碳水化合物、金屬、荷 爾蒙、適合體、縮氨酸及該材料的個别接受器之接受性材料。 Mavas C.\WINS0FT\專渺Jtooi 〇8〜\〇843VpK 〇〇1 〇843 d〇c2〇〇3删 21 587171 21.如申請專利範園第12項的方法,其中感興趣的分析物選自至少其中一 、細菌;酵母菌;眞菌;病毒;風濕性因素;IgG、IgM、IgA、IgD以及igE抗 體;癌胚抗原;鏈球菌群A抗原;病毒抗原;與自體免疫疾病、過敏原、腫 瘤抗原有關的抗原;鏈球菌群B抗原、HIV I或HIV II抗原;或對這此 及其他病毒的宿主感應(抗體);特定對rSV的抗原或對病毒的宿主感 應(抗體);抗原;酵素;荷爾蒙;多醣類;蛋白質;油脂;碳水化合物;藥品或核 酸,奈瑟氏球菌屬組A、B、C、Y及Wsub 135、鏈球菌群肺炎、大腸 桿菌、嗜血桿菌屬流行性感冒類型A/B;衍生自微生物的抗原;psA(前 列腺特異抗原)及CRp(C_反應蛋白質)抗原;半抗原丨濫用藥品;治療性藥 品;環境藥劑;以及肝炎的特有抗原。 22·如申請專利範圍帛I2項的方法,其進一步&含定義爲多數在理想圖案 中於遮罩所露出的地區,露出地區定義爲未活化地區的圖案。 23·如申請專利範圍第12項的方法,其中感光劑爲光酸劑。 24·如申請專利範圍第I2項的方法,其中感光劑爲光氧化劑。 25·如申請專利範圍帛I2項的方法,其中感光劑適合作爲酵化物構件上的 一層0Mavis-C:\WINS〇FT\$^IJ\PkOO 1,08~\0843\PK-001 -0843. doc2003/8/21 22
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-
2002
- 2002-05-03 US US10/139,013 patent/US7214530B2/en not_active Expired - Fee Related
-
2003
- 2003-04-15 AU AU2003221964A patent/AU2003221964A1/en not_active Abandoned
- 2003-04-15 WO PCT/US2003/011746 patent/WO2003093820A1/en not_active Application Discontinuation
- 2003-04-30 TW TW092110106A patent/TW587171B/zh not_active IP Right Cessation
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2007
- 2007-05-07 US US11/800,538 patent/US7695979B2/en not_active Expired - Fee Related
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US7214530B2 (en) | 2007-05-08 |
US20030207256A1 (en) | 2003-11-06 |
AU2003221964A1 (en) | 2003-11-17 |
WO2003093820A1 (en) | 2003-11-13 |
US7695979B2 (en) | 2010-04-13 |
US20080026454A1 (en) | 2008-01-31 |
TW200307812A (en) | 2003-12-16 |
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