TWI220927B - Method for producing a micro-carrier - Google Patents

Method for producing a micro-carrier Download PDF

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TWI220927B
TWI220927B TW089109106A TW89109106A TWI220927B TW I220927 B TWI220927 B TW I220927B TW 089109106 A TW089109106 A TW 089109106A TW 89109106 A TW89109106 A TW 89109106A TW I220927 B TWI220927 B TW I220927B
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carrier
micro
biological
bar code
manufacturing
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TW089109106A
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Rong-Seng Chang
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Rong-Seng Chang
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Priority to TW089109106A priority Critical patent/TWI220927B/zh
Priority to US09/728,317 priority patent/US6350620B2/en
Priority to DE10100819A priority patent/DE10100819C2/de
Priority to US09/847,481 priority patent/US20010041338A1/en
Priority to US10/156,719 priority patent/US20030059804A1/en
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Publication of TWI220927B publication Critical patent/TWI220927B/zh

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    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
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    • G03F7/00Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/0017Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor for the production of embossing, cutting or similar devices; for the production of casting means
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    • Y10S435/00Chemistry: molecular biology and microbiology
    • Y10S435/961Chemistry: molecular biology and microbiology including a step of forming, releasing, or exposing the antigen or forming the hapten-immunogenic carrier complex or the antigen per se
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    • Y10S435/97Test strip or test slide
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10S436/00Chemistry: analytical and immunological testing
    • Y10S436/823Immunogenic carrier or carrier per se
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    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/25Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/25375Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]

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Description

1220927 玖、發明說明: 【發明所屬之技術領域】 本發明係一種生產生物載體的方法,特別是關於一種用以生 產奈米微米大小之生物載體以利用該生物載體檢測其對應的生物 體的方法。 【先前技術】 生物科技是目前極受目屬目的新興科技產業,利用分子生物技 術、生物細胞或其他代謝物質來製造產品的技術,並可應用在醫 藥、農藥、環保、製造與產程開發.、海洋與水產養殖等產業上, 應用範圍相當的廣泛。 而將生物科技與電子科技結合在一起亦是日受重視的一種趨 勢,其中,最引人注意的即是生物晶片(biOChip)(包括基因晶片, 蛋白質晶片,細菌晶片等)今以去氧核醣核酸晶片(DNA Chip)爲例, 去氧核醣核酸晶片即基因晶片,其材料並不侷限於砂,也包括玻 璃、植物纖維質、膠質與有機聚合物等材料。基因晶片是在一指 甲般大小的晶片上粘附多種不同序列的基因小片段,整齊排列成 陣,可容納高達數萬種基因核酸片段,使用者係根據不同的硏究 目的而選擇不同的基因晶片。 其中,上述之基因晶片乃是將不同基因組排列吸附在晶片上, 然後再浸泡螢光染色之不知名待測某基因液體之中,若螢光染色 之基因和基因晶片上某特定基因配對,則可結合反應,在晶片上 留滯發光,而後再以顯微鏡觀看其發光位置則可識別此位置欲置 1220927 之基因,其成對之部分即是螢光染色之基因,進而得知待測基因 屬於何種基因生物。 但此種生物晶片在大量生產之設計下,要在晶片上塗佈有數 千種不同的基因生物,又怕太靠近之二基因生物互相混合,而造 成檢測不正確,故每一生物晶片在精密度的控制必須相當精確, 再者,控制精密度係需要十分昂貴之儀器,相當昂貴,侷限了使 用者之條件。但隨著分子生物技術的發展,開發更有效率、低成 本以及具有低使用條件之核酸資料庫與核酸序列檢測技術係爲當 務之急。上述之例在其他生物晶片亦有同樣之問題,因此,本發 · 明即在針對上述之困擾而提出一解決方案。 【發明内容】 本發明提供一種奈米微米生物載體的製造方法,其係利用積體 電路製程在光罩上製造複數重覆之其上有條碼排列之列之許多各 種微小載體形狀,再以黃光曝光技術製在塗有光阻劑之基板上, 光阻劑洗去後,經蝕刻步驟即可在基板上刻出其上有條碼排列之 列之許多各種微小載體形狀並電鑄翻模成模具如(鎳板模);將 基因可吸附於其上之基材如PS、Nylon包括玻璃、植物纖維質、膠 * 質與有機聚合物等,置於二鎳板間,並以熱壓法壓製,完成有條 碼之微小形生物載體,最後將具生物條碼之載體塗上輔助吸附生 物能力之生物基因生物吸附輔助劑(生物素,biotin)材料等,和 其欲待測生物體所對應的對應生物體混合〔此對應的生物體先和 抗生物性蛋白(avidm)結合’因抗生物性蛋白(avidm)與生物吸 附輔助劑(生物素,biotin)很容易吸附在一起,故對應生物體和 條碼載子可結合在一起〕’以製成各種不同帶有記號之生物載體。 7 1220927 而生物體測試方法則是利用數種上述生物載體,使其與有染螢光 色的不知名待測生物體結合,進而以影像辨識技術辨別發光載體 上之條碼,即可得知待測生物體屬於何種已知生物體。 以下藉由具體實施例配合所附的圖式詳加說明,當更容易瞭 解本發明之目的、技術內容、特點及其所達成之功效。 ^ 【實施方式】 本發明之主要特點係在將生物科技與積體電路結合,以製造出一 φ 種生物載體,以及利用該生物載體來檢測未知基因的測試方法。 一種生物載體的製造方法係包含下列步驟:首先,微小載體 欲吸附的生物體名稱以條碼表示,其係以積體電路製程先在光罩 (mask)上製造形成其上有複數重覆之條碼(barcode)許多各種 微小載體形狀,然後再將之以黃光曝光技術製在塗有光阻劑之基 板上,光阻劑洗去後,經蝕刻步驟即可在該基板上刻出許多各種 微小載體形狀,並電鑄成模具(如:鎳板);將微小載體之材料如包 · 括玻璃、植物纖維質、膠質與有機聚合物置於模具(如:鎳板)間, 且使條碼紋係向內’並以熱壓法、冷凝法或光固化之方法完成有 條碼之微小各種形狀生物載體’於生物載體上塗佈一層透明的生 物吸附輔助劑(生物素’ bl0tin) ’以便將具生物丨 1 条碼之該載體和 其所欲測之所對應的生物體混合並結合在一起’製成帶有記號之 生物載體〔對應生物體先和抗生物性蛋白(avidm)結合’而基因 吸附輔助劑(生物素,biotin)與抗生物性蛋白(avidin)有強結合 力,故可吸附對應生物體〕。因此’使用者可以依據此法製成一
R 1220927 瓶內含有數種帶有條碼之生物載體。 在上述生物載體之形成過程中,置於模具(如:鎳板)之間的材 料更可以紫外光光敏膠置於刻有條碼記號之模具(如:鎳板)上,如 阿拉伯膠粒,再以紫外光照射使其固化,則亦可形成半球狀一再 以上板刻有條碼之模具(如:鎳板)壓製成餅形之具有條碼的該生物 載體。 其中,該微小各種形狀生物載體粒亦可由製程中在光罩上把 修 餅形或其他形狀和條紋一次劃好,如第一圖所示,以曝光触刻法 製成模具,再用射出、熱壓法、冷凝法或光固畫法或印刷法一體 製成。如各粒子之間還有相連則可以習知的雷射光罩或掃描切割 之方法切斷。此外亦可利用雷射直接投影在材料基板上(如 PMMA)直接燒製成具有基因條碼之微小載體 另外,上述之生物載體除以條碼來分辨生物外,本發明更可 以載體之形狀、大小、色彩等載體作爲生物體之代碼 φ ,可分爲下列三類:一、形狀:前述之生物載體爲球體形 ,亦可改用矩形體或多邊形體,如矩形之長寬値不一樣則可代表 某一生物體,或三角形之三邊長不一樣、或多邊形邊長不一樣等 皆可代表各種不同之生物體。二、大小:如大球代表一種生物體, 小球代表另一種’以球體之直徑大小不同來代表不同的生物體。 三、色彩··以各種顏色之球體代表不同生物體,如紅、黃、藍、 白係代表四種不同的生物體,以上述同樣的顯微鏡連接電腦,並 1220927 利用影像識別技術,即可對上列各載體進行識別及計數。 再者,以上不同形狀、大小及條碼之例子亦可用微奈米機械 技術之黃光曝光光罩等方法製造模仁10,如第一圖所示 ,並以模具射出或熱壓法之方法製成。形成後之粒子12因極小, 故會被卡在模10內,因此,可通以負靜電並在其上之一帶有正電 靜電之收集板14將其吸出脫模,如第二圖所示;至於粒子與粒子 之間相連之繞道則可利用滾動擠壓之方法折斷之如各粒子之間還鲁 有相連則可以習知的雷射光罩或掃描切割之方法切斷。此外亦可 利用雷射直接投影在材料基板上(如PMMA)直接燒製成具有基 因條碼之微小載體,可利用半導體製程直接在矽或玻璃基板上蝕 刻帶有條碼之微小載體,粒子若帶有棒狀折斷之繞道,在識別時 可利用軟體去除分辨之。 本發明之方法不需要昂貴之設備,且可彈性自行調配已知生 物體載體之數目及種類,小實驗室即可自行調配,譬如只要五種 _ 已知基因,則準備五小瓶已有條碼之生物載體 ,並混合成一瓶即可。反之,習知生物晶片則因固定了基因數目’ 如某生物晶片一片中有一千種基因,若要購買只有五種基因的晶 片,因量太小廠商不能爲顧客只做一片只有五種基因之晶片’但 用此一片中有一千種基因的晶片又太貴,因此,不若本發明之方 法有彈性、便宜。是故,本創明係兼顧方便、具彈性、便宜功效’ 一般小實驗室即可自行完成基因測試,故可將生物體如基因、蛋 1220927 白質測試工程普遍化,以便可快速普遍的推行生物科技。 以 上所述實施例僅係爲說明本發明之技術思想及特點 ,其目的在使熟習此項技藝之人士能夠瞭解本發明之內容並據以 實施,當不能以之限定本發明之專利範圍,即大凡依本發明所揭 示之精神所作之均等變化或修飾,仍應涵蓋在本發明之專利範圍 內。 【圖式簡單說明】 10模仁 12粒子 11光罩 14收集板 第一圖爲本發明製作生物載體之模仁的實施例。 第二圖爲本發明製作生物載體之示意圖。

Claims (1)

1220927 拾、申請專利範圍: 1·一種奈米微米生物載體的製造方法,包括下列步驟: 將該微奈米級之微小載體欲吸附的生物名稱以條碼表示,再以積 體電路製程,在微奈米光罩上形成許多各種微小載體形狀,其中 有條碼排列之許多各種形狀之微小載體外形;再將之以黃光曝光 技術製在塗有光阻劑之基板上;洗去光阻劑後,經蝕刻即在該基 板上刻出許多各種微小載體形狀,其中有條碼排列之許多各種形 $ 狀之微小載體外形,並電鑄成一模多穴之模具;將該載體置於一 模多穴之模具中,並以熱壓法壓製形成有條碼之微小各種形狀載 體;於該生物載體上塗佈一層透明生物基因吸附輔助劑(生物素, biotin);以及將具基因條碼並塗有基因吸附輔助劑(生物素,b1〇tm) 之該載體和其所對應的結有抗生物性蛋白(avKlm )之基因吸附結 合,製成各種不同帶有記號之基因載體。 2. 如申請專利範圍第1項所述之奈米微米生物載體的製造方法,其 鲁 中,置於模具二鎳板之間的該球體更可以紫外光光敏膠體置於 該刻有條碼模具上,再以紫外光照射固化,而形成有條碼之該 生物載體。 3. 如申請專利範圍第1項所述之奈米微米生物載體的製造方法,其 中,該微小生物載體亦可由製程中在光罩上把餅形或其他形狀 和條碼一次劃好,以曝光飩刻法製成模具,再用射出或熱壓法 一體製成。 4. 如申請專利範圍第1項所述之奈米微米生物載體的製造方法,其 1220927 中,該生·物載體除以條碼來分辨生物體外,更可以載體之各種 形狀、大小、色彩單獨或互相配合作爲生物體之代碼。 5·如申請專利範圍第1項所述之奈米微米生物載體的製造方法,其 中’該射出法或熱壓法更可以冷凝法或光固化法或代替之。 6·如申請專利範圍第1項所述之奈米微米生物載體的製造方法, 其中模具可爲一模多穴,其中所述之微奈米光罩可利用雷射照 射此光罩直接在材料基板上(如PMMA)直接燒製帶有條碼之微 小載體。 7.如申請專利範圍第1項所述之奈米微米生物載體的製造方法, 可利用半導體製程直接在矽或玻璃基板上蝕刻帶有條碼之微小 載體。
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US20010041338A1 (en) 2001-11-15
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US6350620B2 (en) 2002-02-26

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