TWI599774B - 過敏原檢測裝置及平台 - Google Patents
過敏原檢測裝置及平台 Download PDFInfo
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Description
本發明係關於一種過敏原檢測裝置及平台,特別是一種具有一微流體晶片以及一過敏原微陣列晶片的檢測裝置及應用該檢測裝置之平台。
過敏反應係指人體免疫系統的體液或細胞因過敏原引起的發炎性反應,輕則造成患者不適,重則會造成組織的傷害甚至死亡。臺灣地區常見的過敏性疾病包括氣喘、過敏性鼻炎及花粉症等,而過敏原可能是蛋白質或小分子之化學物質,來源可為環境物質、藥物、環境微生物、食物等,隨著現今社會現代化的發展,過敏原的種類不僅繁多更有日漸增加的趨勢。根據世界過敏組織的統計,全球有過敏情況之患者約占人口3至4成,且數目仍在持續增加中。
目前已存在之檢測過敏原之方式係以酵素聯結免疫吸附分析法(Enzyme-linked immunosorbent assay,ELISA)為主,然而,ELISA需先將待測檢體以加熱與離心等前處理,會造成過敏原溶解度降低、變性及喪失抗原性等缺點,影響量測之精確度,且ELISA分析儀器所需之試劑量大,導致受檢者所負擔之檢測費用昂貴。較新出現的檢測技術是利用微陣列技
術將不同種類的過敏原點製於材料表面上,再將受測者之血清樣品與過敏原做反應,惟,此種微陣列技術在反應測試時,仍需人工手動操作並且步驟十分繁瑣,不利於過敏原檢測之廣泛的應用以及推廣。目前市面上仍缺少一種可自動化、高效率、且可節省檢體與試劑用量與時間之過敏原檢測的技術。
緣此,本發明之一目的係提供一種過敏原檢測裝置,用以結合至一過敏原微陣列晶片,該過敏原微陣列晶片設置一微陣列區,該裝置包含:一微流體晶片,係包含一氣體控制層以及一液體流道層,其中該氣體控制層包含至少一個氣體控制入口,該液體流道層包含至少一液體注入口與一反應區;以及一夾持元件,具有一收容空間,該收容空間收容該微流體晶片,且該夾持元件包含至少一夾持機構,該夾持機構夾持該微流體晶片,俾使該反應區對準且密合該微陣列區。該反應區之面積不小於該微陣列區。在本發明之一較佳實施例中,該夾持元件包含一上蓋體與至少一夾持機構,該上蓋體形成該收容空間;該微流體晶片進一步包含一防漏側壁,該防漏側壁係設置於該液體流道層且於該微流體晶片與該過敏原微陣列晶片結合時防止液體側漏。該微陣列區包含至少一個過敏原蛋白。
本發明之另一目的係提供一種晶片檢測平台,用以檢測一過敏原微陣列晶片,該晶片檢測平台包含:一本發明之過敏原檢測裝置;以及一控制系統,該控制系統包含一氣壓控制系統與一溫度控制系統;其中,該控制系統係設置為自動化地執行一微流體晶片中一檢體或一試劑與該過敏原微陣列晶片中一過敏原蛋白之混合或結合反應。在本發明之一實施
中,該氣壓控制系統包含至少一氣壓源,以及一或多個電磁氣壓控制閥;該溫度控制系統包含至少一熱源產生器,以及一導熱組件。該檢體係選自於由血液、血清、血漿、尿液、腦脊髓液、淚液、唾液、咽喉上皮細胞、痰、淋巴、透析液、灌洗液、生物器官或組織培養物衍生的液體、或其任意組合所組成之群組;該試劑係選自於由二級抗體、緩衝液、或其任意組合所組成之群組。在本發明之一較佳實施例中,該晶片檢測平台係降低該檢體之使用量至少35%、降低該試劑之使用量至少50%、且縮短該晶片檢測時間至少50%。
以下將配合圖式進一步說明本發明的實施方式,下述所列舉的實施例係用以闡明本發明之發明特點及應用,而非以限定本發明之範圍,任何熟習此技藝者,在不脫離本發明之精神和範圍內,當可做些許更動與潤飾,因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
1‧‧‧過敏原檢測裝置
10‧‧‧微流體晶片
11‧‧‧氣體控制層
111‧‧‧氣體控制入口
112‧‧‧液體注入口
113‧‧‧廢體抽取口
12‧‧‧液體流道層
120‧‧‧防漏側壁
121‧‧‧反應區
13‧‧‧過敏原微陣列晶片
131‧‧‧微陣列區
132‧‧‧基材
14‧‧‧夾持元件
141‧‧‧上蓋體
142‧‧‧夾持機構
1421‧‧‧固定部
143‧‧‧收容空間
60‧‧‧控制系統
601‧‧‧控制電路
602‧‧‧電源
61‧‧‧氣壓控制系統
611‧‧‧氣壓源
612‧‧‧電磁氣壓控制閥
62‧‧‧溫度控制系統
621‧‧‧熱源產生器
622‧‧‧導熱組件
63‧‧‧熱絕緣支
第1圖係本發明過敏原檢測裝置之***視圖。
第2圖係本發明微流體晶片的氣體控制層與液體流道層之結合俯視圖。
第3圖係本發明過敏原檢測裝置中夾持元件之透視圖。
第4圖係本發明夾持元件結合微流體晶片、過敏原微陣列晶片之***視圖。
第5圖係本發明微流體晶片中液體流道層的翻面視角圖。
第6圖係本發明過敏原檢測裝置結合控制系統自動化操作之示意圖。
本發明提供一種過敏原檢測裝置,其用以結合至市面上可取得之過敏原微陣列晶片。首先,本發明過敏原檢測裝置包含一微流體晶片以及一夾持元件,該微流體晶片包括氣體控制層與液體流道層,該夾持元件用以將該微流體晶片之反應區係與該過敏原微陣列晶片之微陣列區對準且密合,有效地利用市面上面取得之任何過敏原微陣列晶片,達到快速及準確之過敏原檢測。接著,本發明過敏原檢測裝置透過與一控制系統連結可自動化地執行過敏原檢測,包括檢體/試劑之混合/結合反應,以及反應溫度控制,並且可顯著降低該檢體/試劑之使用量,亦可縮短檢測所需的時間。
「微流體晶片」、「晶片」一詞在本文中可互換使用,以表示一獨立的整合單元,其具有一微流體反應器、一個或多個微流體流道、及一個或多個閥門(valve)。微流體晶片亦典型地具有其他微流體組件,例如:泵浦(pump)、槽(chamber)、混合器(mixer)、及其類似的組件。微流體晶片通常係由合成橡膠(elastomer)、玻璃(glass)、或矽(silicon)製成。典型地,微流體晶片係為具有一高度相較於長度及寬度為短的盒狀物,然而,晶片亦可為任意形狀,例如:立方體、圓柱體、或其他。
「抗體」一詞在本文中係包括但不限於一實質上由免疫球蛋白編碼的多胜肽或多胜肽片段,其專一性地結合且辨識一被測物(抗原)。
「檢體」一詞,係任何衍生自病患之生物檢體,包括但不限於生物液體,諸如:血液、血清、血漿、尿液、腦脊髓液、淚液、唾液、淋巴、透析液、灌洗液及其他液體樣本,以及生物來源之細胞及組織。該
辭彙亦包括細胞或其衍生之細胞及其子代,包括培養物中之細胞、細胞上清液及細胞裂解物。該辭彙亦包括器官或組織培養物衍生的液體、組生檢樣本、腫瘤生檢樣本、糞便樣本、萃取自生理組織之液體以及分離自固態組織、組織切片及細胞裂解物之細胞。此一定義涵括在其獲得之後以任何方式操作之樣本,諸如:以試劑處理、溶解或使其富含某些組成份,諸如:聚核苷酸或胜肽;亦包括病患樣本之衛生物及區份。病患樣本可用於診斷或其他監測分析;亦可應用於來自非人類哺乳動物之生物檢體。該檢體可來自人類病患或非人類哺乳動物。
如第1圖所示,本發明提供一種過敏原檢測裝置1,用以結合至一過敏原微陣列晶片13,該過敏原微陣列晶片13係為市面上可取得之微陣列晶片,通常而言,市售用於檢測過敏原之微陣列晶片包括固定於一基材132上的一微陣列區131,且該微陣列區131包括至少一個過敏原蛋白。本發明過敏原檢測裝置1包含一微流體晶片10以及一夾持元件14,其中該微流體晶片10,係包含一氣體控制層11以及一液體流道層12。該夾持元件14包含一上蓋體141以及一夾持機構142,該夾持機構進一步包括至少一固定部1421,用以將該夾持機構142固定於一平台。
如第1圖及第2圖所示,該微流體晶片10係由設置於上方之一氣體控制層11與設置於下方之一液體流道層12組合而成。就較佳的微流體晶片10而言,該氣體控制層11設置有至少一個氣體控制入口111,該氣體控制入口111係用於控制氣體輸入/排出該氣體控制層11,產生氣壓差以使該液
體流道層12彈性形變而推動液體傳輸。該液體流道層12則設置有至少一液體注入口112與一反應區121,於使用時可同時或不同時將一檢體或至少一試劑通過氣體控制層11中與該液體注入口112相對應的開口注入該反應區121。再者,該液體流道層12亦設置有廢體抽取口(waste outlet)113,藉由與上述氣體控制層11組合,可將反應後或過多之反應溶液排除。
如第3圖所示,該夾持元件14具有一上蓋體141及至少一夾持機構142,該上蓋體141具有兩側翼部並形成一收容空間143,上蓋體141並具有與上述氣體控制入口111、液體注入口112相對應的開口,該收容空間143收容該微流體晶片10。該夾持元件14包含的夾持機構142較佳為可旋轉或可拆卸式,且該夾持機構142較佳設置於該上蓋體141之兩側。該夾持機構142具有對應該兩側翼部之凹陷部以及兩樞轉扣持部,在兩側翼部與對應的凹陷部互相嵌合後,該兩樞轉扣持部分別扣持該上蓋體141的兩側翼部。該夾持機構進一步包括至少一固定部1421,用以將該夾持機構142固定於一平台。由於本發明之微流體晶片10的氣體控制層11與液體流道層12係可由高分子聚合物(例如:聚雙甲基矽氧烷,polydimethylsiloxane,PDMS)所製成為彈性材質,而該夾持元件14之上蓋體141係可由塑膠或玻璃等製成,質地較硬,故,藉由該夾持元件14以夾持該微流體晶片10,俾使該微流體晶片10之反應區121對準且密合位於下方之該微陣列晶片13之該微陣列區131。
此外,該反應區121的面積較佳為不小於該微陣列區131,且如第4圖所示,在使用本發明過敏原檢測裝置時,該夾持元件14係由上往下與本發明之微流體晶片10組合,故,該收容空間143較佳為具有至少大於該微流體晶片10之長度、寬度、與厚度。該夾持元件14的上蓋體141之兩側較
佳具有翼部,而夾持機構142較佳具有對應的凹陷部,使兩者可互相嵌合。該夾持機構進一步包括至少一固定部1421,用以將該夾持機構142固定於一平台。利用夾持元件14所具有的收容空間143收容該微流體晶片10,並利用夾持機構142夾持該上蓋體141、該微流體晶片10,俾使該微流體晶片10之該反應區121對準且密合設置於下方之該過敏原微陣列晶片13之該微陣列區131,使得注入該微流體晶片10之檢體或試劑可與該微陣列區131上的至少一個過敏原蛋白接觸。因此,本發明過敏原檢測裝置可結合的過敏原微陣列晶片13之選擇可不限於其材質、尺寸、或過敏原蛋白種類等,並可直接運用既有的微陣列晶片。
另一方面,為了達到該微流體晶片10與該過敏原微陣列晶片13更緊密地接合並防止注入該液體流道層12之檢體或試劑溢出,如第5圖翻面視角圖所示,本發明設計一防漏側壁120,係設置於該液體流道層12的至少一個邊上。使用時,該具有彈性的液體流道層12是向下與該過敏原微陣列晶片結合(即,該防漏側壁120係朝下),請參見第4圖,藉由防漏側壁120可包住硬質的過敏原微陣列晶片,而該防漏側壁120之高度較佳為略大於該過敏原微陣列晶片13之厚度,較佳約為1毫米。
本發明過敏原檢測裝置可進一步與一控制系統整合,而可自動化地執行過敏原檢測,如第6圖所示,該控制系統60包括一氣壓控制系統61與一溫度控制系統62。藉由與一電源供應器602連接之控制電路601,本發明之控制系統60可在執行檢測時自動化地調控該氣壓控制系統61與該溫
度控制系統62。該氣壓控制系統61係與該微流體晶片10連接,且包括至少一個氣壓源611與一或多個電磁氣壓控制閥612。該電源供應器602產生之電流通過控制電路601至該電磁氣壓控制閥612,造成該電磁氣壓控制閥612的開啟或關閉,進而使得該微流體晶片10的氣體控制層11中的氣壓改變,產生該液體流道層12彈性形變而推動液體傳輸。另一方面,該溫度控制系統62包括至少一熱源產生器621與一導熱組件622,且亦可藉由該控制電路601調控。該熱源產生器621係可為任何可產生穩定熱能之儀器,而該導熱組件622亦可為任何具有良好導熱性之材料,該導熱組件622較佳為具有大於該反應區121與該微陣列區131之尺寸。
另一方面,如第6圖所示,該夾持機構142較佳為可旋轉或可拆卸式,且該夾持機構142較佳設置於該上蓋體141之兩側。當使用該夾持元件14於本發明自動化過敏原檢測系統時,該夾持機構142與複數個熱絕緣支架63組合,該熱絕緣支架63係設置為可調整高低以使該過敏原微陣列晶片13靠近或遠離該導熱組件622,達到更精準的反應溫度控制。
藉由與上述控制系統整合,本發明之過敏原檢測裝置可自動化地執行抗體/抗原之混合/結合反應。首先,製備反應物如:樣品血清(濃度比為1:9)、第一清洗緩衝液、第二清先緩衝液、二級抗體(濃度比為1:1500)、以及逆滲透水各130μL,並由該液體注入口加入至該微流體晶片。接著,無需任何人為操作,藉由該控制系統,本發明之裝置可自動化地執行各反應物於該反應區之混合與結合反應,舉例而言,可先將樣本血清注入該反應區20秒、抽離反應區20秒並進行30個週期(共20分鐘),接著以清洗緩衝溶液重複清洗3次,即將該第一清洗緩衝液與第二清洗緩衝液各個分別注入該
反應區10秒、抽離反應區5秒並進行4個週期(共1分鐘),之後將二級抗體注入該反應區20秒、抽離反應區20秒並進行30個週期(共20分鐘),再次以上述反應週期並以清洗緩衝溶液重複清洗3次,最後以逆滲透水清洗1次,即將逆滲透水注入該反應區10秒、抽離反應區5秒並進行1個週期(共1分鐘)。本發明過敏原檢測裝置中,該微流體晶片中檢體/試劑之流速較佳為81.32±2.33μL/秒。
如上所述,本發明自動化的過敏原檢測僅需檢體/試劑各130μL,與傳統人工手動操作需要約200至300μL相比,可節省約35%至57%之檢體/試劑用量;而本發明自動化的過敏原檢測整體所需時間為45分鐘,與傳統人工手動操作整體所需的90分鐘相比,可縮短50%的檢測時間。另一方面,檢測之準確度(CV值)係以微陣列上1組3個相同蛋白的抗原點所產生之螢光訊號值的標準差除以平均值計算,數值愈小代表檢測愈準確,而本發明自動化的過敏原檢測之CV值係為20%,與傳統人工手動操作之CV值為30%相比明顯較佳,說明本發明過敏原檢測裝置不僅可自動化地執行準確的過敏原檢測,更可減少檢體/試劑的用量,同時大幅縮短檢測所需的時間。
綜上所述,本發明之過敏原檢測裝置可直接應用既有的微陣列晶片,並且使用與夾持元件,有效地使微流體晶片之反應區與微陣列晶片上含有過敏原蛋白之微陣列區密合,達到快速且準確之過敏原檢測。本發明之過敏原檢測裝置亦透過與控制系統整合,自動化地執行過敏原檢測,較傳統人工手動操作之過敏原檢測方法顯著地節省檢體/試劑之使用量,以及縮短檢測所需的時間,故,可避免傳統人工操作之不穩定性且大幅降低檢測的成本,不僅可應用於既有過敏原微陣列晶片快速、準確、經
濟之檢測及實驗室免疫學研究,亦可提供未來開發不同的檢測晶片一更有效的使用方法。
本發明所提供之過敏原檢測裝置及過敏原微陣列晶片檢測平台確具產業上之利用價值,惟以上之敘述僅為本發明之較佳實施例說明,凡精於此項技藝者當可依據上述之說明而作其它種種之改良,惟這些改變仍屬於本發明之精神及以下所界定之專利範圍中。
1‧‧‧過敏原檢測裝置
10‧‧‧微流體晶片
11‧‧‧氣體控制層
111‧‧‧氣體控制入口
112‧‧‧液體注入口
113‧‧‧廢體抽取口
12‧‧‧液體流道層
121‧‧‧反應區
13‧‧‧過敏原微陣列晶片
131‧‧‧微陣列區
132‧‧‧基材
14‧‧‧夾持元件
141‧‧‧上蓋體
142‧‧‧夾持機構
1421‧‧‧固定部
143‧‧‧收容空間
Claims (11)
- 一種過敏原檢測裝置,用以結合至一過敏原微陣列晶片,該過敏原微陣列晶片設置一微陣列區,該裝置包含:一微流體晶片,係由一氣體控制層以及一液體流道層組合,其中該氣體控制層包含複數個氣體控制入口,該液體流道層包含複數個液體注入口、一面積不小於該微陣列區之反應區、及連接該液體注入口與該反應區之各自獨立的複數個連通微流道;以及一夾持元件,具有一收容空間,該收容空間收容該微流體晶片,且該夾持元件包含一具有兩側翼部之上蓋體與至少一夾持機構,該夾持機構夾持該微流體晶片至該過敏原微陣列晶片設置該微陣列區的側面上,俾使該反應區對準且密合該微陣列區,其中該夾持機構具有對應該兩側翼部之凹陷部、兩樞轉扣持部以及至少一固定部,在兩側翼部與對應的凹陷部互相嵌合後,該兩樞轉扣持部分別扣持該上蓋體的兩側翼部,該固定部用以將該夾持機構固定於一平台;其中該微流體晶片進一步包含一防漏側壁,該防漏側壁係設置於該液體流道層的側邊上,且於該微流體晶片與該過敏原微陣列晶片結合時防止液體側漏。
- 如申請專利範圍第1項所述之裝置,其中該上蓋體形成該收容空間,該收容空間收容該微流體晶片。
- 如申請專利範圍第1項所述之裝置,其中該微陣列區包含至少一個過敏原蛋白。
- 一種晶片檢測平台,用以檢測一過敏原微陣列晶片,該晶片檢測平台包含: 一如申請專利範圍第1項所述之裝置;以及一控制系統,該控制系統包含一氣壓控制系統與一溫度控制系統;其中,該控制系統係設置為自動化地執行一微流體晶片中一檢體或一試劑與該過敏原微陣列晶片中一過敏原蛋白之混合或結合反應。
- 如申請專利範圍第4項所述之晶片檢測平台,其中該氣壓控制系統包含至少一氣壓源,以及一或多個電磁氣壓控制閥。
- 如申請專利範圍第4項所述之晶片檢測平台,其中該溫度控制系統包含至少一熱源產生器,以及一導熱組件。
- 如申請專利範圍第4項所述之裝置,其中該檢體係選自於由血液、血清、血漿、尿液、腦脊髓液、淚液、唾液、咽喉上皮細胞、痰、淋巴、透析液、灌洗液、生物器官或組織培養物衍生的液體、或其任意組合所組成之群組。
- 如引請專利範圍第4項所述之裝置,其中該試劑係選自於由二級抗體、緩衝液、或其任意組合所組成之群組。
- 如申請專利範圍第4項所述之晶片檢測平台,其中該晶片檢測平台係降低該檢體之使用量至少35%。
- 如申請專利範圍第4項所述之晶片檢測平台,其中該晶片檢測平台係降低該試劑之使用量至少50%。
- 如申請專利範圍第4項所述之晶片檢測平台,其中該晶片檢測平台係縮短該晶片檢測時間至少50%。
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US11261414B2 (en) * | 2016-11-14 | 2022-03-01 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Apparatus for reconfiguration of components in a microphysiological system |
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TWI675106B (zh) * | 2018-03-21 | 2019-10-21 | 緯創資通股份有限公司 | 液體處理模組、液體檢測系統及利用液體處理模組進行檢測的檢測方法 |
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CN110538680A (zh) * | 2019-08-19 | 2019-12-06 | 昆山汇先医药技术有限公司 | 一种微流控样品处理设备 |
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