JP7104033B2 - 生物学的又は化学的分析のためのバイオセンサ及びその製造方法 - Google Patents
生物学的又は化学的分析のためのバイオセンサ及びその製造方法 Download PDFInfo
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Description
本願は、2016年11月3日に出願された米国仮特許出願第62/416,813号の優先権を主張し、その内容は参照によりその全体が組み込まれる。
本発明は、一般に、生物学的又は化学的分析のためのバイオセンサに関し、より具体的には、裏面照射型(BSI)相補型金属酸化膜半導体(CMOS)イメージセンサを含むバイオセンサ、及びその製造方法に関する。
CMOSイメージセンサは、デジタルカメラ、医療用画像機器、レーダー装置などを含む電子画像装置に使用される。集積回路及び一連のフォトダイオードを用いて、CMOSイメージセンサは、光を捕らえて、それを電気信号に変換することができる。
本発明の実施形態は、生物学的又は化学的分析のための改良されたバイオセンサを提供することによって、従来のアプローチに関連した欠点に対処する。本発明の実施形態によれば、BSI CMOSイメージセンサは、試料の蛍光又は化学発光を効果的に分析及び測定するために使用することができる。この測定値を使用して、試料の同定に役立てることができる。本発明の実施形態はまた、生物学的又は化学的分析のための改良されたバイオセンサを製造する方法を提供する。本明細書で使用される場合、用語「バイオセンサ」は、生物学的分子内の又は生物学的分子に結合した発光物質を測定するための装置を指すために使用することができ、斯かる生物学的分子は、特にDNA及び分枝鎖又はそうでなければ誘導体化された核酸によって例示される核酸高分子である。本明細書で使用される場合、用語「核酸高分子」は、例えば、DNB又は一本鎖の実施形態を指し得る。
以下の図面を参照して、本発明の例示的な実施形態を以下に詳述する:
図1~13は、本発明の実施形態によるバイオセンサの製造の様々な段階を説明している。製造及び構成の他の実施形態は、この説明から当業者には明らかであろう。それゆえ、以下の記載は説明的であり、限定的ではないことが意図される。
図2は、いくつかの実施形態による、(例えば、高分子又は高分子複合体の化学発光を検出するための)生物学的又は化学的分析に使用することができるバイオセンサ200を示す。バイオセンサ200は、裏面照射型CMOSイメージセンサ100を含む。裏面照射型CMOSイメージセンサ100は、電子回路層(第1の誘電体層110及び金属配線113からなる)並びに電子回路層上の光検知層(基板層115及びフォトダイオード117からなる)を含む。フォトダイオード117は、電気信号が、フォトダイオード117から電子回路層に、及びいくつかの実施形態では、外部装置に伝達され得るように、電子回路層と接触していてもよい。受光面は、電子回路層とは反対側であるフォトダイオード117の面によって規定される(すなわち、第1のパッシベーション層120と接触している表面)。
したがって、図8Aは、いくつかの実施形態による、生物学的又は化学的分析に使用することができるバイオセンサ800を示す。バイオセンサ800は、裏面照射型CMOSイメージセンサ100を含んでもよい。裏面照射型CMOSイメージセンサ100は、電子回路層(第1の誘電体層110及び金属配線113からなる)並びに電子回路層上の光検知層(基板層115及びフォトダイオード117からなる)を含む。フォトダイオード117は、電気信号が、フォトダイオード117から電子回路層に、及びいくつかの実施形態では、外部装置に伝達され得るように、電子回路層と接触していてもよい。受光面は、電子回路層とは反対側であるフォトダイオード117の面によって規定される(すなわち、第1のパッシベーション層120と接触している表面)。
したがって、図9は、いくつかの実施形態による、生物学的又は化学的分析に使用することができるバイオセンサ900を示す。バイオセンサ900は、裏面照射型CMOSイメージセンサ100を含む。裏面照射型CMOSイメージセンサ100は、電子回路層(第1の誘電体層110及び金属配線113からなる)並びに電子回路層上の光検知層(基板層115及びフォトダイオード117からなる)を含む。フォトダイオード117は、電気信号が、フォトダイオード117から電子回路層に、及びいくつかの実施形態では、外部装置に伝達され得るように、電子回路層と接触していてもよい。受光面は、電子回路層とは反対側であるフォトダイオード117の面によって規定される(すなわち、第1のパッシベーション層120と接触している表面)。
したがって、図13は、いくつかの実施形態による、生物学的又は化学的分析に使用することができるバイオセンサ1300を示す。バイオセンサ1300は、裏面照射型CMOSイメージセンサ100を含む。裏面照射型CMOSイメージセンサ100は、電子回路層(第1の誘電体層110及び金属配線113からなる)並びに電子回路層上の光検知層(基板層115及びフォトダイオード117からなる)を含む。電気信号が、フォトダイオード117から電子回路層に、及びいくつかの実施形態では、外部装置に伝達され得るように、フォトダイオード117は電子回路層と接触していてもよい。受光面は、電子回路層とは反対側であるフォトダイオード117の面によって規定される(すなわち、第1のパッシベーション層120と接触している表面)。
図2、8A、9及び13に関して上述したように、生物学的又は化学的試料は、カラーフィルター材料127B及びフォトダイオード117の上の記載されたバイオセンサのそれぞれの上に配置され得る。生物学的又は化学的試料は、任意の数の構成要素を含んでもよい。例えば、試料は、核酸高分子(例えば、DNA、RNA等)、タンパク質などを含み得る。試料は、遺伝子配列、DNA-DNAハイブリダイゼーション、一塩基多型、タンパク質相互作用、ペプチド相互作用、抗原-抗体相互作用、グルコースモニタリング、コレステロールモニタリングなどを決定するために分析され得る。
本実施例は、BSI CISセンサが、表面に付着した光子放出分子からの弱い信号を検出するために使用され得ることを実証する。本発明者らは、図9に記載されたように、ただしカラーフィルター層は無しに(すなわち、要素120、123B、125、及び127Bを欠いて)、バイオセンサを構築した。さらに、表面133Bを疎水性にし、かつ開口部150A/B/Cの底面を親水性にした(従ってDNBが親水性表面に向かって、かつ疎水性表面から離れて分布するように)。
Claims (12)
- バイオセンサであって、以下:
裏面照射型相補型金属酸化膜半導体(CMOS)イメージセンサであって、以下:
電子回路層;及び
前記電子回路層上の光検知層、
を含むイメージセンサ、ここで、前記光検知層は、
基板層と、
前記電子回路層と接触している複数のフォトダイオードとを含み、
ここで、受光面は、前記電子回路層とは反対側の前記複数のフォトダイオードの面によって規定される;
前記複数のフォトダイオードの上のパッシベーション層、ここで、前記パッシベーション層は、酸化物である;並びに
前記受光面上の前記パッシベーション層上に形成された規則的なアレイのスポット、ここで、各スポットは、個別の正に荷電した領域であり、前記領域は、核酸高分子を受けて保持するようにサイズ設定及び/又は官能化され、ここで、前記アレイのスポットの各スポットは、核酸高分子を受けて保持しないように構成されているという意味で不活性である領域によって、他のスポットから分離される、
を含み、
ここで、前記バイオセンサは、ポリマー材料を用いて波長範囲によって光をフィルタリングするように構成されたカラーフィルター層を含まない、バイオセンサ。 - 前記パッシベーション層が、100nm以下の厚さを有する、請求項1に記載のバイオセンサ。
- 請求項1又は2に記載のバイオセンサであって:
前記複数のフォトダイオードはそれぞれ、第1の長さ寸法(linear dimension)によって特徴づけられ;並びに
前記複数のスポットはそれぞれ、第2の長さ寸法によって特徴づけられ、前記第2の長さ寸法は、前記第1の長さ寸法よりも小さい、バイオセンサ。 - 前記電子回路層が、以下:
誘電体層;及び
前記誘電体層において形成された金属配線、ここで、前記金属配線は、前記複数のフォトダイオードを外部装置に結合するように構成される、
を含む、請求項1に記載のバイオセンサ。 - 各スポットが単一のフォトダイオードを覆う、請求項1に記載のバイオセンサ。
- 複数の核酸高分子をさらに含む、請求項1に記載のバイオセンサであって、各核酸高分子が、前記複数のスポットの1つのスポット内に配置されている、バイオセンサ。
- 前記核酸高分子が、ローリングサークル増幅によって生成されたDNAナノボールであるか、又はブリッジポリメラーゼ連鎖反応(PCR)によって生成されたクローンクラスターである、請求項6に記載のバイオセンサ。
- 前記複数のフォトダイオードの各フォトダイオードが、前記複数の核酸高分子の1つの核酸高分子上の化学発光標識から放出された光を検出するように構成されている、請求項1又は6に記載のバイオセンサ。
- 前記光が、スポット上に固定化された核酸高分子にハイブリダイズした化学発光標識プライマー伸長産物から放出される、請求項8に記載のバイオセンサ。
- 励起光源を含まない、請求項1から9のいずれか一項に記載のバイオセンサ。
- 請求項1に記載のバイオセンサを使用するDNA配列決定の方法であって、以下:
核酸高分子内の特定の位置でヌクレオチド塩基を同定する化学発光標識で核酸高分子を標識すること;
裏面照射型相補型金属酸化膜半導体(CMOS)イメージセンサのフォトダイオード上に核酸高分子から放射された化学発光を検出すること;
フォトダイオードで受光された放射光の少なくとも1つのパラメータを測定すること;及び
化学発光標識に対して放射光の少なくとも1つのパラメータを相関させること;並びに
核酸高分子から化学発光標識を除去すること、
を含むプロセスを反復して実施することを含む、方法。 - 前記核酸高分子から放射された化学発光が、ルシフェラーゼに媒介されるルシフェリンのオキシルシフェリンへの変換によって生成される、請求項11に記載の方法。
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