TWI236364B - Percutaneous biological fluid constituent sampling and measurement devices and methods - Google Patents
Percutaneous biological fluid constituent sampling and measurement devices and methods Download PDFInfo
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- TWI236364B TWI236364B TW091112465A TW91112465A TWI236364B TW I236364 B TWI236364 B TW I236364B TW 091112465 A TW091112465 A TW 091112465A TW 91112465 A TW91112465 A TW 91112465A TW I236364 B TWI236364 B TW I236364B
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- biological fluid
- microneedle
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Classifications
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- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
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- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
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Description
1236364 A7 、發明說明 發明範疇 本發明關於經由皮膚之生物流體抽樣及分析物測量, 更特定S之是關於有助於生物流體抽樣之成分轉移介質。 發明背景 生物流體内之分析物的偵測日益重要。分析物偵測檢 驗應用於許多層面,其中包含臨床實驗室職、家用測試 1^此等測試的結果在許多疾病狀態的診斷和管理方面扮 次著重要的角色。一般為人注意的分柝物包含葡萄糖(例 如針對糖尿病管理)、膽固醇等。 咖 種㊉見用以收集金液樣本供分析物判定的技術為刺 、皮膚至:>、到皮下層内接近下層血管以便在身體表面上造 成局邛出血。然後將取得的血液集中在一小試管内以進行 運达及讓測試設備分析,此等測試設備通常是成一有一讓 血液樣本放上之試劑測試條的手持儀器形式。指尖是此種4 =液收集方法最常使用的地方,因為有大量的小血管位在 ,尖内:此方法有著非常痛的重大缺點,因為指尖的皮下 組織有著濃密的神經末端。f要經常性監測_受測物的患 經濟部智慧財產局員工消費合作社印製 避做Jk液抽樣的情事並不罕見。以糖尿病患者為例, f於依循醫嘱經常測量其葡萄糖水準會導致缺乏適當控制 葡萄糖水準所需的資訊。失去控制的葡萄糖水準可能非常 危險且甚至危及性命。此種血液抽樣技術亦有著讓患者感 染矛傳遞疾病的潛在危險,特別是以_高頻率基準進行 者。此技術的問題因能用於經常性血液抽樣的皮膚表面有 限而加重。 A7 B7 1236364 五、發明說明(2) 點,二術及伴隨著嚴重疼痛之其他技術的缺 用微型針或類似結構物以接近皮膚内 膚内未達皮下層的深度以使患者的痛感減小。2入皮 流體抽樣亚測試叫定目標成分的濃度。間質^間質 =的濃度代表著其他體液(例如血液)内之該成 二=微型針描樣系統有一缺點在於因為 質流體歧-场6毫米汞柱㈣壓環境,經常要== 些機械或真空構件組搭配微型穿刺構件。
舉例來說,世界專利申請案w〇 99/27852號揭 真工壓力及/或熱以提高被施予真空或熱之皮膚區 質流體可取得量。真空壓力使得皮膚在真空附近的部八二 間質流體而變得緊端且舰,此有助於在進人皮膚内二 ^取流體。該案揭示另—種方法,其中將L熱元L 定㈣皮膚上方,導致該處關質流體流得較快,從而能 在每單位時間内收集到較多間質流體。此 經濟部智慧財產局員工消費合作社印製 過去亦開發出避免將皮膚完全刺穿的其他偵蜊裝置。 其取代方式為用一較被動的方式、、弄破(disrupted)夕 皮膚的外層(稱為角質層)以提供皮膚内之生物流體的出 入口或抽取處。此等方式包含利用振盪能量、對皮膚表面 施加化學試劑等。舉例來說,世界專利申靖案w〇 98/34541號揭示一振盪濃縮器(例如一針或金屬線)的使 用,其定位為離皮膚表面一段距離且藉由一電機變換器使 其振動。該針浸沒於一安置為與皮膚接觸且内裝〜液態介 -4- 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 χ 297公釐) 1236364 A7 B7 五、發明說明(3) 質的容器内。此針的機械性振動轉移給液體,在皮膚表面 上產生足以弄破角質層之細胞結構的流體動力學應力。世 界專利申請案W0 97/42888號和W0 98/00193號亦揭示利 用超音波振動之間質流體偵測方法。 因此,儘管在分析物測試之領域的工作已然達成,有 一後續關注目標在於更貼合於相關市場需求之新分析物偵 測方法的確認。而特別令人感興趣的是一實用、可產品 化、精確、易於使用、且安全而有效之極小侵入性分析物 偵測系統的開發。4 相關文獻 相關美國專利包含:5, 582, 184號;5, 746, 217號; 5, 820, 570 號;5, 942, 102 號;6, 091,975 號及 6, 162, 611 號。其他相關專利文件和公告包含:世界專利wo 97/00441 號;WO 97/42888 號;WO 98/00193 號;WO, 98/34541 號;WO 99/13336 號;WO 99/27852 號;WO 99/64580 號;WO 00/35530 號;WO 00/57177 號及 WO 00/74765A1 號。 經濟部智慧財產局員工消費合作社印製 發明概述 本發明提出經由皮膚之生物流體抽樣及分析物測量的 系統和裝置及其使用方法。本發明之一特徵在於一成分轉 移介質的存在,該成分轉移介質抽樣並轉移於皮膚内取得 之生物流體的至少目標成分至一用來測量該流體樣本内之 目標成分的電化學巢室。本發明適用於取得生物流體(例 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公楚)
1236364 如血液和間質流體),以及出現在所取得生物流體内之多 種分析物(例如葡萄糖、膽固醇、電解質、藥物、或草 藥、以及類似物)的_和測量。本發明特別適合間質: 體成分(例如葡萄糖)之抽樣和測量。 整體而言,本發明之抽樣及測量裝置包含一用來提供 生物流體之出人口的長形皮膚穿刺構件組,至少一個成一 成分轉移介質形式的抽樣構件組,及—成—電化學測量巢 室形式與該成分轉移介質處於流體連·係的測量構件 組0 該皮膚穿刺構件組包含至少一微型針,該微型針定義 -穿過微型針結_部之至少—部分的域環形孔或渠道 且在-末稍端有-出人開口讓—或多個生物流體成分經此 開口進入裝㈣。在許多實_中,該皮膚㈣構件組包 括此等微型針之一陣列。 經濟部智慧財產局員工消費合作社印製 ,該電化學測量巢室包括^位於微型針結構内且/或定 義微型針結構的有間隔卫作電極和參考電極。該等電極間 的區域絲為反應區,真正的分析物濃度測量是在此區内 進行。在某些實_巾,此餘對為_地定位且相互成 同心間隔關係,其令至少外側電極有一中空 造且至 少局部定義微型針結構。内側電極定位於該外極之筒 壁==亦可為-筒狀構造(―内部填充—中央蕊心材料 圓筒或是一實心圓筒)。在其他實施例令,該電化 子巢至以定位為大致_於微型針之縱向⑽之二個平行 間隔平面的形狀義微型針結構之基部端。 在作業中,以該電化學巢室之電極其令之一做為參考
j236364 五 經濟部智慧財產局員工消費合作社印製 、發明說明(5) 號產生構件組經此電提供 輪出信號徂名— η 竹I自於感測器 輪出信號供予一严哚枝 π木目於感測器之 仇在ρ署:收構件組。較佳來說,該參考電極 所取=部且作電極位在裝置頂部。此輪出信號代表 侍生物流體内之目標分析物的濃度。 以協:Ϊ:電化學巢室内使用一氧化還原試劑系統或材料 以要目標分析物。所用的狀氧化還原試劑材料是 以要測頁之目標分析物為基礎做選擇。 疋 =構件組之成分轉移介f佔據兩電極間之區域(稱 移介質每一微型針渠道的至少—部分。該成分轉 質疋由一親水性的水凝膠或膠體材料或母 對生物流體内之離子和陰離子粒子有—親和力。必要時可 將該膠體母質構形為僅轉移有—低於指定分子量之分子量 的粒子。該膠體的作用為將出現在—微型針之出入開口= 目標生物流體成分轉移至反應區内。易言之,目標成分在, 組織内之_成分的濃度與膠體母質内之該成分的濃度達到 平衡之前持續經由膠體母質遷移。與一單純依靠施加於生 物流體之毛細作用力將生物流體轉移至電化學巢室内的中 空微型針做比較,本發明之成分轉移介質可構形(亦即以 一完全飽和狀態出現)為排除所取得生物流體内所含之水 和其他流體的轉移而僅轉移生物流體的成分。電化學巢室 的構造會從剩餘的測試成分選出目標成分。 本發明之膠體母質的特徵為一濃度梯度,其依據一階 系統改變。此谷許错由一階糸統之指數特性計算離子性和 非離子性的成分濃度。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
I 2363 64
發明說明(6) 本發明之感測裝置可做為一包含一控制該感測裝置之 構件組之分析物感測系統的一部分工作。明確地說為提供 控制單元,其中控制構件組與該感測裝置電耦接且其作 用為對電化學巢室產生並發送輸入信號以及自該巢室接收 ,出信號。這些機能是由一程式化在該控制單元内的軟體 ,异法執行,其在從電化學巢室收到一輸出信號之後自動 地計算並判定生物樣本内之目標分析物的濃度。 本發明之一範例方法涉及使用至少一個包括一或多個 中空微型針的本發明感測裝置,每一微型針有一開口末稍 端定義-通往-體_之電化學巢㈣成分轉移通道。一 親水性膠體材料充滿於微型針及電化學巢室的内部。該微 型針插人皮膚内達-預定深度,較佳為—避賴及神經末 端和血管㈣度。其次,至少將出現在微型針開口末稍端 之生物流體樣本的目標成分蕊吸至膠體材料岐轉移至該 電化學巢室的反應區内。然後在該卫作電極與參考電極之, 間,行-電化學測量,此-測量提供_代表該樣本内之成 以度的電信號。織由獲得的電信號推斷患者血液_ 成分的濃度。錢可將-代表此濃度之財化數值顯示在 广可利用一身為該裝置之-部分(例如程式 化於出現在該裝置内的控制單元内) a…η ^ 平關)的軟體演算法判定由 该控制早το對該巢室發出的信號位準 物的濃度水準。 及用以推斷目標分析 裝置、系統和方法適用於多種分析物之分析 ,度測1 ’且特別適合用於間質流體之葡萄糖濃度的測 -8- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱) 裝 訂 線 經濟部智慧財產局員工消費合作社印製 1236364 A7 B7 五、發明說明(7) 圖式簡單說明 圖1包含圖1A、IB、1C和1D,其中圖1A為一本發明 微型針之長向局部斷開剖視圖,圖1B為圖1A微型針沿箭 頭b-b取得的剖面圖,圖1C為圖1A微型針沿箭頭c-c取 得的剖面圖,且圖1D為圖1A微型針沿箭頭d-d取得的頂 視圖; 一— 圖2包含圖2A和圖2B,其中圖2A為本發明微型針之 另一實施例的長而局部斷開剖視圖,圖2B為圖2A微型針 沿箭頭b-b取得的剖面圖; 圖3為本發明之膠體母質之一階系統的曲線圖;且 圖4為一本發明之抽樣及測量裝置的簡圖。 較佳實施例詳細說明 經濟部智慧財產局員工消費合作社印製 本發明提出經由皮膚之生物流體(例如間質流體)抽, 樣及分析物測量的感測裝置和系統及其使用方法。本發明 適用於生物流體(例如血液和間質流體)内可見之成分的 抽樣,且適用於多樣不同分析物(例如葡萄糖、膽固醇、 電解質、藥物、禁藥及類似物)的偵測和測量。 整體而言,本發明之裝置包含一皮膚穿刺構件組,一 個成一成分轉移介質形式的生物流體成分抽樣構件組,及 一成一電化學測量巢室形式與該成分轉移介質處於流體連 通關係的成分濃度測量構件組。 在說明本發明之前,要瞭解到本發明並不侷限於本說 明書所提的實施例,因為可就這些實施例做變異而仍在所 冬 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 五 發明說明 附申請專利範圍項的範圍之内 在提出一數值範圍的情 該範圍之上限與下限之間的每_區32==涵蓋在 清楚敘述則計至下限之單: 力則後文未 圍或該所述範圍的區間内二2其他所述範 獨立地包令在較小範圍内亦屬於本發明,受 盆中限制約束。在所述範圍包含此等限: 制之任二者㈣圍Γ兄中,本發明亦涵蓋排除此等内含限 除=另有定義’本說明書使用的所有技術性和科學性 子。3的⑤、義起習本發g㈣屬技藝者通常 相似於或等效於本說明書所揭示之二目 ^用於本發明之實施或測試,較佳的方法和材料為本 說明書所揭示。本說明書提及的所有公告案皆以制 式併入本文中以揭示並敘述與所引用之公告案有關的方法 及/或材料。 A要注意到在本說明書及申請專利範圍中,單數表示法 、、一 ”或V'該^ (譯註··原文之A a夕、 ' 抑和 the )若於前後文内未以其他方式明確指出則包含複 數個對象。舉例來說,、、一測試條(a test strip),,的 說法包含複數個此等測試條,且、、該處理器(the
Pr〇cessor)"的說法包含一或多個處理器及熟習此技藝 者所知的等效物,諸如此類。 -10- 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 1236364
五、發明說明(9 ^說明書用的公告案僅止於本申請案之申請日之前 的内谷。本說日轉並無隻字>!語能解釋為承認本發明不是 早於本貝為客知發明之該等公告案定名。此外,本說明書 引用之該等A告案的日期可能不同於真實公告日期,真實 曰期可能需要個別確認。
皮膚穿刺構件組 皮膚牙刺構件組包括至少一個用來刺穿皮膚至一讓疼 痛和出金量減至表少—(最好不存在)之深度的微型穿刺構 =取好成-微型針形式)。是讀型針最好是刺到有神 ㈣仏上i此,可讓此等穿刺構件穿 皮膚層包含真皮、表皮和角質層(亦即表皮的最外層) 錢型針疋義一穿過_具有一讓生物流 微型針内之末稍出入開口之窄丨…胞“:刀丌進入 環形孔或渠道。在本發明==:内部的大致 月之感測裝置的某些實施例中,呤 皮膚牙·她包括鱗_狀—_。 … r===r:=:: ==r:;:===: =1好微及/讀歸_的㈣㈣承受= 微型針及/或微型針陣列可由一絕緣材料、 著一絕緣材料,例如一陶瓷、玻璃、二氡化石夕、塗佈 塑膠及類似物。聚合物類之實例為聚叫㈣類聚σ物、 -11- 本紐尺度適时ϋ國家標準(CNS)A4規格(21〇 χ 29?公楚) ^-------- 1236364
月曰類,聚酯型聚鱗_酮,液晶聚酯類,或以上的組合物。 陶瓷類的實例為氧化鋁,碳化矽及氧化锆。適合的金屬材 料包含不銹鋼,鈦,貴金屬或其合金以及類似物。 今參照圖1和2說明本發明之範例微型針的整體構 造。圖1A和2A分別繪出微型針1〇〇和200,此等微型針 有一大致沿縱向軸線成平直狀態且有一大致圓形橫斷面的 構造。然其可運用任何適當的橫斷面型態,其中非侷限性 包含其他環狀形狀(例如橢圓形和長圓形)或是多邊形構 造(例如方形和痖形)。一微型針在其最厚點的外徑約介 於200微米至3〇〇微米,通常約不超過350微米。在某些 實施例中,該外徑通常約為250微米。 本發明之一重要觀點為其排除或至少大幅減少一患者 在抽樣程序中遭受的疼痛和出血。因此,微型針之穿刺長 度和直徑必須在某些特定範圍内以達成此目的。當然,這 些數值會因想要取樣的生物流體類型(例如間質流體、血, 液或二者)以及接受測試之特定患者之皮膚層的厚度等而 異。 經濟部智慧財產局員工消費合作社印製 皮膚包含三個不同的層:一稱為表皮的頂層,一稱為 真皮的中間層及一稱為皮下層的底層。表皮的厚度約為6〇 微米至120微米且包括四個不同的層:一稱為角質層的1〇 微米至20微米外層,接著是粒層、表皮生髮層及生長 層。角質層含有充滿了交聯角質素和角質層透明質束且受 一脂質細胞外母質包圍的細胞。内三層總括稱為活表皮且 總厚度在大約50微米至100微米的範圍内。該活表皮負 責對真皮往來擴散代謝產物。表皮不含血球或神經末端。 -12- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1236364 A7 B7 五、發明說明(U) 真皮比表皮厚得多,其厚度大約在2000微米至3000微米 的範圍内。真皮層大致由一結締組織(包含膠原纖維)之 濃密底床和遍及該等纖維散佈的間質流體組成。在真皮層 底下為皮下組織,其内含有微血管以及皮膚内之神經末端 的絕大多數。 因此在許多實施例中,本發明之微型針最好具有在完 全刺入皮膚内時不延伸至比真皮層更深處的穿刺長度以使 疼痛減至最小;然其在有特定抽樣用途之需求時可為較 長。微型針的長发對直徑比例為決定此等微型針之^«最佳 長度的另一考量因素。為了有效且無創傷地刺穿皮膚,微 塑針的長度通常是微型針直徑的至少約五倍,然可為較多 或較少。最小微型針直徑是依電極間之必要間距以及電化 學巢至之其他組件的直徑而定。 經濟部智慧財產局員工消費合作社印製 因此,此等微型針的長度大致在約500微米至4〇〇() 微米的範圍内,通常約介於6〇〇微米至3000微米間,更· 常見的是約介於1〇〇〇微米至2000微米之間;然此等長度 會因患者而異,端視接受測試之特定患者的皮膚層厚度而 定。儘管此等微型針可具有比目標皮膚層之深度更長的長 度,該微型針可以刺入皮膚内一小於該微型針結構之長度 的深度(稱為穿刺長度)。因此,為了使患者的疼痛減至 最少,微型針之穿刺長度約在50微米至4000微米範圍内 的穿刺長度,更常見的是約100微米至3000微米。舉例 來說,就僅需刺入表皮層内的抽樣應用來說,微型針之穿 刺長度通常約介於50微米至120微米之間。就需要刺入 但不超過真皮層内的抽樣應用來說,微型針的穿刺長度通 -13- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 1236364
五、發明說明(12 常約介於2000微米至30〇〇微米之間。 微型針100和200分別在末稍端1〇4和2〇4以一有一 斜面或切片構造的針尖102和2〇2 (如圖1D所示)了結使 其更易於刺穿皮膚。然針尖1〇2和2〇2可具有其他適當構 造,例如不縮細且在一垂直於微型針縱向軸線之平面内定 義一邊緣的構造(圖中未示)。 本發明可運用成一陣列形式之任何適當數量微盤針。 所用微型針的數量會因許多因素而定,其中包含要偵測的 物質、微型針將插入的身體表面位置、取樣點、流體容積 及類似因素。該微型針陣列可包含具有不同形狀、長度、 寬度和針尖構造的微型針。 電化學巢室 經濟部智慧財產局員工消費合作社印製 本發明之電化學巢室包含一工作電極和一參考電極之 一電極排列,其對已抽樣的生物流體成分提供一輸入參考, 信號且提供一代表該已抽樣流體内之目標成分或分析物之 濃度的輸出信號。此二電極成一間隔關係使一電極之一表 面面向另一電極之一表面。該二電極間之空隙定義〆反應 區,已抽樣的成分為轉移至此反應區内並接受測試以求取 一目標分析物的濃度。 本發明可運用分析物偵測及測量之技藝中為人所知的 多種不同電化學系統,其中包含電流計量(亦即測量電 流)、電量計量(亦即測量電荷)或電位計量(亦即測量 電壓)的系統。這些類型的電化學測量系統之實例更見於 美國專利第 4, 224, 125 號,4, 545, 382 號和 5, 266, Π9 -14- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1236364 ________- — B7 五、發明說明(13 ) ^ ^^ 號;以及世界專利W0 97/18465號和W0 99/49307號,以 上專利的内容以引用的方式併入本文中。 圖1和2繪出本發明之電化學巢室的二個範例實施 例。特定言之,圖1A-C繪出一電化學巢室實施例,其有 二個完全罩在微型針内的同軸校直同心間隔電極。圖2a 和B繪出一電化學巢室實施例,其在微型針之一基部端有 二個平行間隔的大致平坦電極。 — 今參照圖1A-C,微型針1〇〇包含一電化學巢室提供代 表從一已抽樣生‘流體成分内測量所得之分析物濃度的電 信號。該電化學巢室包括以相互成同心關係之方式棑列的 多個不同組件或層。更明確地說,此同心排列亦可稱為周 圍的或同轴的。 經濟部智慧財產局員工消費合作社印製 參照圖1A之縱長剖面和圖1B之橫斷面,微型針1〇〇 包含一實心線蕊106和一外鍍層114。實心線蕊ι〇β為微 型針結構提供剛性且可為相鄰電極的一部分。外鍵層H4, 可為不銹鋼或類似物製成。在線蕊106與外鑛層114 4間 為本發明的電化學巢室,此電化學巢室由内而外包含一第 一或内電極108、一第二或外電極112及一介於電極之間 的反應區110。第二電極112和外鑛層114延伸至定義微 型針100之邊緣116和針尖102。 如圖1C沿圖1A箭頭c-c取得的末稍端基部圖所示, 第一或内電極108覆蓋實心線蕊106之基部端;然該基部 端可為外露的。第一電極108和實心線蕊1〇6 一同延伸至 一點118 (末稍端104的基部),其中此二層具有大致相 互齊平的末稍邊緣。這些齊平的邊緣定義一内腔部分J20 -15- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1236364 B7 五、發明說明(Η 的封閉基部端,該内腔部分有〜丄& 刀,由第二電極112和外铲屛 114定義延伸至末稍邊緣lie〜 卜锻層 的腔壁。 末稍開口(如圖U所示) 由内腔120和反應區110在微型針⑽内部定義的門 :或中空空間填充著-成分轉移介質(在此如前所ir 親水性膠體材料)。此膠體的作用為吸收出現= ,生物流體的成分並將其轉移至内腔—潘韻後送入反應 區110内。 圖1電化學巢室之各纪件的適當尺寸如下。一般而 言,外電極112的長度可與微型針之穿刺長度大致相同, 因此依期望的穿刺長度而定通常約不超過麵微米或更 小。更常見的外電極長度為介於約麵微米至3_微 米,最好大約2000微米。内電極可與外電極等長,但最 好是略短。内電極的長度通常約比外電極短2〇%且大致約 不超過3200微米或更小,通常約介於8〇〇微米至24〇〇微‘ 米之間,更常見的是約16〇〇微米。 經濟部智慧財產局員工消費合作社印製 實心線蕊106之直徑是在約8〇微米至1〇〇微米的範 圍内,通常約不超過120微米。在某些實施例中,其直徑 通常約為90微米。第一電極1〇8有一筒狀構造(但其他 構造亦為可行)’其厚度在約7〇埃至2〇〇埃的範圍内, 通常約不超過300埃。因此,由於第一電極造形為圍繞蕊 心106,其外徑略大於蕊心丨〇6的外徑。第二電極112亦 有一筒狀構造(但其他構造亦為可行),其厚度是在約70 埃至200埃的範圍内,通常約不超過別〇埃。兩電極間之 反應區或空隙亦有一筒狀構造(但其他構造亦為可行), -16- 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 1236364 A7 B7 五、發明說明(I5) 其厚度是在約50埃至80埃的範圍内,通常約不超過200 埃。電鍍上第二電極112之薄外管114的厚度在約12微 米至20微米的範圍内,通常約不超過25微米。因此,微 型針100的總外徑大致約不超過200微米,通常在約250 微米至300微米的範圍内,更常見的是約不超過350微 米。内腔120的容積大致在約20 nL至140 nL的範圍 内,通常約不超過250 nL。 今參照圖2A和B,圖中緣出一有一由外鐘層214和内 腔220定義之管狀構造的微型針200。内腔220的容積大 致在約25 nL至280 nL的範圍内,更常見的是在約25 nL 至160 nL的範圍内。不同於圖1之微型針100,其全部長 度都是中空的。微型針200可具有與前述相同或相似的長 度和直徑尺寸,然可代以較小的尺寸,因為其電化學巢室 位在微型針内腔220以外而非罩在内部。 經濟部智慧財產局員工消費合作社印製 一由平行的平坦電極208和212定義之電化學巢室定, 位於微型針200的基部端205。因此,該電化學巢室在微 型針插入一患者的皮膚内之後仍留在皮膚表面之外。電極 208定義一表面從微型針200之基部端205繞周延伸。此 時電極208是成一圓環形式,如圖2B所示,然其可具有 任何適當形狀如方形或矩形。電極212與電極208相隔不 遠,在其間定義一空隙當作電化學巢室的反應區210。該 空隙大致在約50微米至80微米的範圍内,通常不會超過 150微米。電極212最好有一呼應於電極208之形狀和大 小的形狀和大小。此時電極212最好有一圓盤形狀及一與 電極208之外徑相同的直徑。此直徑尺寸大致在約600微 -17- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 1236364 、發明說明 米至800微米的範圍内,通常不會超過1公釐。電極1⑽ 之内徑最好符合外鍍層214的直徑,因而具有前文提及、 數值。 的 至少面向微型針100和200内之反應區Π1Λ ”和Ζ10的 圖1和圖2電極表面是由高傳導性金屬製成,例如纪 金、鉑、銀、銥、碳、銦摻雜氧化錫、不銹鋼和類似物、 或以上材料之一組合。最常使用的金屬為金、 4白或鈀。雖 d整個電極可為金屬製成,每一電極可為由一在表面上具 有電極之一金屬纟且件薄層(例如一電鍍金屬層) /、 撐或背襯基板構成。 、敗入支 親水性膠體材料 本發明之抽樣構件組的成分轉移介質可彳 片J 用反應區 Π0和21〇的全部容積以及每一微型針内腔12〇和2別' 至少一部分,然亦可為完全填滿内腔。該成分轉移介新田 好是由-對水有高親和力(亦極微高吸水性)的:二二:’ 材料或母質製成。親水性膠體有助於預先調節電極^重組 試劑材料以準備目標分析物之電化學測量。 、、、 經濟部智慧財產局員工消費合作社印製 轉移介質吸收流體(特別是水)的能力與轉移介質在 暴露於此流體之前的飽和程度息息相關。為了減少微型針 插入或施加於皮膚的時間’成分轉移介質最好在微型針插 入皮膚内之前處於-完全飽和狀態。因此,僅會轉移生物 流體内所含的非流質成分(包含一或多個目標成分),藉 此免除生物流體之初期轉移的時間。舉例來說,由於間^ 流體大約有98%是水,通過膠體之擴散時間的縮減在某些 -18 - 本紙張尺度適用中國國家標準(CNS)A4規格⑽x 297公复) 1236364
經濟部智慧財產局員工消費合作社印製
應用可倉b會很明顯。 在能夠擴散通過膠體母質的成分之間,其到達反應區 的速率會因成分的分子大小而異。整體而言,分子越小則 通過膠體的擴散速率越快。由於—般常見的分析物如葡萄 糖、電解質、抗壞錢、尿酸等具有小分子,此等分析物 會比間質W體内由較大分子組成之其他組份較快擴散通過 膠體母質。 A^) 選定的水凝膠之濃度動力學是一階系統。因此,生物 流體的成分轉移速率以及分析物濃度水準更可_。此一 階系統以下列方程式及圖3之曲線圖表示: c=c0 其中c是膠體材料内之分析物濃度,(:。為間質流體f ^分析7度,t為測量進行時間,且T為系 ΐ:=::值依下列因素而定:⑴水凝咖 微型針10°和之邊
m目t積);⑴水凝膠容積;< 圄3^4^、摘用特定水郷材料的傳遞特性。 ⑴'苴中t !緣出上式一階系統。相依軸線代表時I 發明之水凝膠材料膚的時間點。就適合' _微型針之末稍開口的生物流 =超:r之時一。= 微型針移離:膚4=Γ统,可在達成平衡之前 患者體内的分析物濃度水準(二基= -19- 1236364 A7 B7 五、發明說明(18 與間質流體間之接觸持續時間可受到控制(亦即為固定 的)且以前述的一階方程式導出C〇。 適合做為本發明之成分轉移介質的膠體材料包含··由 天然生成之聚合物製成的天然膠體,例如瓊脂膠楗、明 膠、黏多糖類、澱粉類及類似物;至少部分由^成聚合物 製成的合成膠體,例如任何中性水可溶解的聚合物_或聚 合電解質(亦即在溶解於>;^時會形成離子電荷的合成或天 然聚合物),例如聚乙烯吡咯烷酮 '聚乙二醇、聚丙烯 酸、聚乙烯醇、致丙烯醯胺、及以上的共聚物。 試劑 經濟部智慧財產局員工消費合作社印製 為了略過已抽樣生物流體内其他成分挑出並感妒經選 為接受分析之目標分析物或成分,通常在電化學菜家之反 應區内使用一氧化還原試劑。該氧化還原試劑材料通常沈 積在兩電極之面向表面的至少其中之一上,藉以讓出現在< 反應區内的生物流體與該試劑材料產生化學反應。因此, 試劑最好是藉由浸塗法塗佈或沈積在表面上。所用試劑是 以横測對象的分析物為基礎做選擇。將試劑系統與對應成 分或分析物的交互作用運用於電化學測量協定以^ + Z + 内之目標分析物或成分的濃度。 i 出現在反應區内之試劑系統通常包含至少_ 目標分析物氧化的一種酵素或多種酵素。易士< 系統之酵素組份是由單一分析物氧化酵素或__ 析物氧化之兩種或更多酵素的集合構成。適用^使目“分 -20- 的酵素包含 介體。在許多實施例中,該試劑系統之酵素^件酵素和一 該試劑 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) Ϊ236364
氧化酶、脫氫酶'脂酶、激活酶、心肌黃酶、奎諾蛋白 (qumoproteins)及類似物。出現在反應區内之指定酵 素依包化學測試條所設計要<貞測的特定分析物而定,其中 代表性的酵素包含:葡萄糖氧化酶,葡萄糖脫氫酶,膽固 醇醋醋酶,膽固醇氧化酶,脂蛋白脂酶,甘油激活酶,三 磷酸甘油酯氧化酶,乳酸鹽氧化酶,乳酸鹽脫氫酶,焦葡 萄酸鹽氧化酶,酒精氧化酶,膽紅質氧化酶,尿酸酶及類 似物。在目標分析物為葡萄糖的許多較佳實施例中,試劑 系統之酵素組份爲一使葡萄糖氧化的酵素(例如一葡萄糖 氧化酶或葡萄糖脫氫酶)。 試劑系統之第二組份為一介體組份,其由一或多種介 體劑組成。此技藝中有多種不同介體劑為人所熟知且包 含:氰鐵酸鹽,吩嗪硫酸乙酯,吩嗪硫酸甲酯,苯二胺, 1-甲氧基-吩嗉硫酸甲酯,2, 6-二甲基-1,4-苯醌,2, 5-二 氯-1,4苯醌’二茂鐵衍生物,鐵雙吡啶錯合物,釕錯合物, 及類似物。在以葡萄糖為目標分析物且葡萄糖氧化酵素或 葡萄糖脫氫酵素為酵素組份的實施例中,較佳的介體為氰 鐵酸鹽。其他可出現在反應區内的試劑包含緩衝劑(例如 經濟部智慧財產局員工消費合作社印製 棒康酸鹽 '檸檬酸鹽、礙酸鹽),、、G00(j”緩衝物及類似 物。 試劑一般是以脫水形式出現。各組份的量可能各自不 同’其中酵素組份的量通常為約0.1%至10%重量百分 比。 感測系統 -21- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1236364
五、發明說明(20 ) 你中在本發明之感測系統中,電化學巢室之參考電極和工 作電極與-控制構件組電聯絡,該=二 後由輸出信號推室接收輸出信誠 件組提供-在該二析物濃度。易言之,控制構 ==所r流變化與出現在電化學二之分 度,最好Γ字其數,。然後推斷出患者血液内的會析物濃 組。 亍化數值以一輸出信號供予一顯示構件 控制ΐ=說如顯示構件組為一體地罩在-手持式 … L 所示。該控制單元最好亦提供-將- -夕微w-微型針陣定或抓持於—適合拿在 進^特㈣抽樣和測量制之位置和排列的構件組。 圖。3’= 5Vf中顯示本發明之—感測系統50的簡 系統50包含一手持式控制單元犯及一如 感=地安裝在控制單元52之末稍端54的感測裝置10。, 二;衣置一1〇包含本發明微型針(例如圖1 * 2的微型針 —較4之陣列。控制單元52有一殼體56,此殼體最好由 :樂級塑性材料製成,具有低矮型構造,罩住一用來控 :置10之測量構件組(亦即產生並發送給微型針 ,化學巢室的輸入參考信號且從該巢室接收輸出测量信 k的構件組(圖中未示)。一程式化在控制單元52内 ^敕體演算法在收到該輸出信號之後自動地計算並判定生 2本内之目標分析物的濃度。然後將濃度水準(連同其 他想要的資訊)發送至一外接顯示構件組或螢幕58將資 1236364
讯顯示給«者。提供控制 靖對制量的 52感測裝置10在電氣和實體兩方面皆轉接於控制單元 5 =者間的電聯絡是藉由褒置1Q上的傳導性接觸件 圖中:不):及控制單元52内的對應導電軌條(圖中 =立。較佳來說,裝置1〇和控制單元52是由一快 機構(許多此類機構韓謂熟知)做實體耗接,、 侍用過的裝置能輕易卸下更換。控制單元犯通常 可多=使用的且V與任何數量的本發明❹道置一同^ I測Ϊ些特性有助於以—有效且快速的方式取得多個樣本 使用方法 本發明亦提出利用本發明之裝置和感測系統判定一生 Β1的方法。有多種不同的分析物· ί貞測,其中代表性的分析物包含 、酒精、及類似物。 (對照圖式),第一步為提供一 針100的感測裝置10。較佳來 規劃(亦即含有適當試劑)以針 10與一能由使用者拿持並控制 I合並接界。控制單元52經程式 。將感測裝置10定位於使用= .用些微壓力使感測裝置之微 内。微型針100插入的深度會取 -23- …——,…係_S)M 規格(21〇Τ^Γϋ^ ~ 1236364 五、發明說明(22 ) " 〜 ~ 決於個別微型針長度或由伴隨著感測裝置1〇用來限制插 入深度的其他構件組決定。 在插入使用者皮膚内之後,該膠體基成分轉移介質藉 由滲透作用將出現在微型針1〇〇之開口針尖1〇2的—些^ 物流體(亦即-生物流體樣本)吸收至個別的微型針⑽ 120内。-旦在反應區内,目標分析物會與選定的試舰 行化學反1»而形成電活性產物。然後藉由任選的介體或是 直接用工作電極108使此等電活性產物氧化或還原。然後 用電極108將結臬的輸出信號位準傳導至控制單元。然後 一程式化於控制單元52内之軟體演算法自動地判定輸出 信號與參考信號之間的差,由此差值推斷出樣本内的分析 物濃度,然後推斷患者血液内之選定分析物的對應濃度水 準。任一或所有上列數值可由顯示構件組或螢幕58顯 示0 一自動計异並判定在一生物樣本及/或患者系統内之, 一選定分析物的濃度使得一使用者僅需將一本發明微型針 插入患者皮膚内然後從一顯示器讀取最終分析物濃度結果 的衣置(例如控制單元52)在標題為、、Sample Detection 經濟部智慧財產局員工消費合作社印製 to Initiate Timing of an Electrochemical Assay"的 美國專利第6, 193,873號有進一步的說明,該專利的内容 以引用的方式併入本文中。 套組 本發明亦提出用以實行本發明方法的套組。本發明之 套組包含至少一個具有一或多個微型針的本發明感測裝 -24- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 1236364 Α7 Β7 五、發明說明(η 置 1組亦可包可與該套組或來自本發明套 置起使用的可多次使用或可 抛式控制單元。此等套組可肖人 3具有長度相同或不同之微 型針之一陣列的裝置。某此套% 一嘗、、且可包含各自裝有相同或不 同試劑的多個感測器。又,在I ^ 在早—微型針陣列内可具備一 種以上的試劑,其中-或多個微型針具備一用來測試第一 目標分析物之第-試劑,且—❹個其他微型針具備用來 測試其他目標分析物的其他試劑。最後,該套組最好包含 利用本發明裝置奴-生理流體内之—分析物濃度的使用 說明。此等使用說明可為在一或多個包裝件、一標籤嵌入 物、或套組内具備的容器以及類似物上。 從以上說明明顯可知本發明易於使用且能以不需要割 開皮膚的方式進行分析物測試而僅有微量或根本沒有疼痛 或出血。因此,本發明對此範疇有卓著的貢獻。 本發明是以吾人認為最為實用且較佳的實施例於本說, 明書中列出說明。然而,應了解到可由此做出在本發明之 範圍内的新發展,而此等明顯的修改在熟習此技藝者閱覽 過本說明書之後即會知曉。 經濟部智慧財產局員工消費合作社印製 儘管本發明適用於許多用途,對眾多生物流體抽樣以 及偵測許多成分類型,本發明迄今主要是就間質流體内之 分析物的偵測做說明,且特別適用於間質流體内之葡萄糖 的偵測。因此,本說明書所揭示之特定裝置和方法和其應 用以及提及的生物流體和成分均視為範例說明而非限制。 達到本說明書所揭示概念之等效意義和範圍内的修改(例 如熟習此技藝者所能輕易想到者)視為是包含在所附申請 •25·
規格(210x297公釐) A7 1236364 B7 五、發明說明(24 ) 專利範圍項的範圍以内。 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 1236364 Λ7 B7 五、發明說明(25 ) 圖式之元件代號說明: 經濟部智慧財產局員工消費合作社印製 代表符號 名稱 10 感測裝置 50 感測系統 52 控制單元 54 控制單元末稍端 56 殼體 58 螢幕 60 控制介面按鈕 100 微型針 102 :針尖 104 末稍端 106 實心線蕊 108 第一(内)電極 110 多孔隔絕物 112 第二(外)電極 114 外艘層 116 邊緣 118 末稍端基部點 120 内腔 200 微型針 202 針尖 204 末稍端 205 基部端 208 電極 210 反應區 212 電極 214 外鍍層 216 邊緣 220 内腔 -27- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
Claims (1)
- 2όψ3^4^ jl/、、申凊專利範圍 專利申請案第91112465號 ROC Patent Application No.91112465 修正後無劃線之申請專利範圍中文本—附件(三) Amended Claims in Chinese - Enel. (ΊΙΡ (民a93年l2月 /日送呈) (Submitted on December J 5 2004) 1. 10 15 20 經濟部智慧財產局員工消費合作社印製 25 -種生物流體成分抽樣及分析物濃度測量的裝置,其 包括: (a) —長形構件,其有一構形為用來刺穿一皮膚 表面及提供生物流體出入口的開口末稍端; (b) 同心間隔的電極,該等電極定位於該長形構 件内定義一用來測量該生物流體内之目標分析物濃度 的電化學巢室;及 (c) 一成分轉移介質,其包括一與該長形構件以 及該電化學巢室成流體連通關係的親水性材料,其中 該成分轉移介負將出現在該長形構件開口末稍端之至 少一生物流體成分轉移至該電化學巢室内。 2. 如申請專利範圍第1項之裝置’其中該長形構件包括 一内腔,其中該開口末稍端提供一通入該内腔之通 道。 3. —種用來抽樣生物流體成分及測量該生物流體内至少 一目標成分的濃度之裝置,其包括: 一第一電極,其有一第一長度; 一第二電極,其有一第二長度大於該第一長度且定 位為同心地包圍該第一電極且有所間隔,其中該第一 電極構形為用來刺穿皮膚;及 一水凝膠材料,其在該第一電極與第二電極間之空 -28 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 91226B-接 1236364 A8 B8 C8 D8 六、申請專利範圍 間内。 4. 如申請專利範圍第3項之裝置,其有一深度不超過真 皮的穿刺長度。 5. 如申請專利範圍第3項之裝置,其中該第二電極有一 5 開口末稍端且在該裝置内定義一空間,其中該空間内 實質填滿該水凝膠材料。 6. —種用來抽樣一生物流體成分且測量該生物流體内之 一目標成分的微型針,其包括: 一蕊心,其有一長度; 10 一第一電極,其同軸地依循包圍該蕊心長度; 一第二電極,其與該第一電極呈同轴地分開且有一 延伸至該蕊心長度以外並終結於一開口針尖的長度; 及 一水凝膠材料,其位於該第一電極與第二電極之 15 間;及 一試劑,其容納在該微型針内,其中該試劑是以該 目標成分為基礎做選擇。 經濟部智慧財產局員工消費合作社印製 7. —種生物流體成分抽樣及分析物濃度測量的裝置,其 包括: 20 (a) —長形中空構件,其有一構形為用來刺穿一 皮膚表面及提供生物流體出入口的開口末稍端以及一 基部端; (b )二個平行間隔的電極’該等電極定位於該長 形中空抽樣構件之基部端且定義一用來測量該生物流 -29 - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 1236364 A8 B8 C8 D8 六、申請專利範圍 體内之分析物濃度的電化學巢室;及 (C) 一成分轉移介質,其包括一與該長形中空構 件以及該電化學巢室成流體連通關係的吸水性材料’ 其中該成分轉移介質將出現在至少一穿刺構件之開口 5 末稍端的生物流體轉移至該電化學巢室内。 8. —種用來從一患者之皮膚抽樣生物流體成分且測量該 生物流體内之一目標成分之系統,該系統包括: (a)至少一微型針,其至少局部為中空且有一用 來讓該生物流體出入的開口末稍端; 10 (b) —伴隨微型針之電化學巢室,該巢室包括相 互有所間隔之一參考電極和一工作電極; (c) 一吸水性膠體母質,其至少部分地包容在該 微型針之中空部分以及該等電極間之空間内;及 (d) —控制單元,其與該電化學巢室電聯絡,該 15 控制單元包括: (1) 對該參考電極發送一參考電信號及從 該工作電極接收一輸出電信號的構件組,及 經濟部智慧財產局員工消費合作社印製 (2) 一軟體演算法,其在收到該輸出電信 號之後自動地計算並判定該生物樣本内之目標 20 成分的濃度。 9. 一種用來判定生物流體内所含之至少一目標成分的濃 度之方法,該方法包括以下步驟: 提供至少一微型針,該微型針包括一開口末稍端及 一内腔; -30 - 本紙張尺度適用令國國家標準(CNS)A4規格(210x297公釐) 1236364 A8 B8 C8 D8 六、申請專利範圍 在該内腔内提供一電化學巢室,該電化學巢室包括 一同心分層的電極構造; 將該微型針之開口末稍端插入皮膚内達一選定的深 度; 5 將出現在該開口末稍端之生物流體樣本内之至少一 目標成分之一樣本經由該内腔轉移至該電化學巢室 内; 對該電化學巢室提供一第一電信號;及 接收一由該電化學巢室產生的第二電信號,其中該 10 第二電信號為該生物流體内之該成分的濃度的代表。 訂 10. —種用來判定生物流體内所含之至少一目標成分的濃 度之方法,該方法包括以下步驟: 提供至少一中空微型針,該微型針包括一開口末稍 端、一開口基部端及一在此二端間延伸的内腔; 15 提供一與該中空微型針成流體連通關係的電化學巢 室,該電化學巢室包括一平行間隔的電極構造,其中 該電極構造大致橫斷於該微型針地定位於該中空微型 針的開口基部端; 經濟部智慧財產局員工消費合作社印製 將該中空微型針之開口末稍端插入皮膚内達一選定 20 的深度; 將出現在該中空微型針之開口末稍端的至少一目標 生物流體成分之一樣本轉移至該電化學巢室内; 對該電化學巢室提供一第一電信號;及 接收一由該電化學巢室產生的第二電信號,其中該 25 第二電信號為該生物流體内之該成分的濃度的代表。 -31 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 x297公釐)
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CN1817297A (zh) | 2006-08-16 |
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AU4445202A (en) | 2002-12-19 |
CZ20022023A3 (cs) | 2003-02-12 |
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