JP6438054B2 - 三次元干渉顕微鏡観察のためのシステムおよび方法 - Google Patents
三次元干渉顕微鏡観察のためのシステムおよび方法 Download PDFInfo
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Description
本出願は、「三次元干渉顕微鏡観察のためのシステムおよび方法(System and Methods for 3-Dimensional Interferometric Microscopy)」という名称で2006年12月21日に出願された米国仮特許出願第60/871,366号ならびに「三次元干渉顕微鏡観察のためのシステムおよび方法(System and Methods for 3-Dimensional Interferometric Microscopy)」という名称で2007年3月27日に出願された米国仮特許出願第60/908,307号(いずれも参照によりその全体が本明細書に援用されるものとする)に基づく優先権を主張する。本出願はまた、「三次元干渉顕微鏡観察のためのシステムおよび方法(System and Methods for 3-Dimensional Interferometric Microscopy)」という名称の米国特許出願第11/961,601号(その全体が参照により本明細書に援用されるものとする)に基づく優先権を主張するものでありかつその継続出願である。
本発明は、一般的には、干渉顕微鏡観察、たとえば、光活性蛍光タンパク質分子から光を内部放射するサンプルのように、空間分解可能な点光源で構成されたもしくは標識されたサンプルの干渉顕微鏡観察、および/または第3の次元(たとえばz座標)で位置情報を決定すると同時に2つの他の次元(たとえばx座標およびy座標)で位置情報を測定するために位相差が測定される干渉顕微鏡観察に関する。
一実施形態では、装置は、複数のディテクターとプロセッサーとを有する光学システムを含む。光学システムは、所与の時間で、各ディテクターで、第1の次元と第1の次元に実質的に直交する第2の次元とで、光源の画像を生成するように構成される。画像の各画像は、光源からの第1の方向の発光と、光源からの第1の方向とは異なる第2の方向の発光と、の干渉に基づく。プロセッサーは、画像に基づいて第3の次元で位置を計算するように構成される。第3の次元は、第1の次元と第2の次元とに実質的に直交する。
広義には、本明細書に記載の1つ以上の実施形態により、公知の光学顕微鏡観察よりも良好な解像度を有する三次元レンダリングを生成することが可能である。いくつかの実施形態では、干渉顕微鏡で位相差を測定することにより、第3の次元(たとえばz座標)で位置情報を決定すると同時に2つの他の次元(たとえばx座標およびy座標)で位置情報を測定することが可能である。いくつかの実施形態では、一群の点光源を含有するサンプル、たとえば、光活性蛍光標識から光を内部放射するサンプルを干渉顕微鏡で測定することが可能である。
E1=A×exp(−ikδ+ikL1+ikL2+iπ/2)、
式中、k=2π/λ。
E2=A×exp(ikδ+ikL1+ikL2)。
E12=1/20.5×(E1±E2)=
1/20.5×(A×exp(−ikδ+ikL1+ikL2+iπ/2)±A×exp(ikδ+ikL1+ikL2))。
I1=1/2×(E1+E2)2=A2×(1+sin(2kδ))。
I2=1/20.5×(E1−E2)2=A2×(1+sin(2kδ+π))。
(I1−I2)/(I1+I2)=sin(4πδ/λ)またはδ=λarcsin((I1−I2)/(I1+I2))/4π
Iij=Gj×(AUi 2+ALi 2+2×βj×AUi×ALi×cos(φi+φj)+Ofsj)
式中、j=0、1、2、…は、多位相干渉計のレッグを表す、
Ij=点光源のjレッグの強度、オフセット補正なし、
βj=j番目のレッグの干渉補正係数、
Gj=j番目のレッグのゲイン、
Ofsj=j番目のレッグのオフセット、
AUi=i番目の点光源の振幅、上側対物レンズ、
ALi=i番目の点光源の振幅、下側対物レンズ、
φj=j番目のレッグの位相シフト、および
φi=点光源(すなわち蛍光分子)の位相。
Ioj=Gj×Ofsj
Iij=Gj×(AUi 2+ALi 2+2×βj×AUi×ALi×cos(φi+φj)+Ofsj) 全振幅:ATi 2=AUi 2+ALi 2
Xi=2×AUi×ALi/ATi 2
Iij=Ioj+Gj×ATi 2(1+βj×Xi×cos(φi+φj))
Ifj(z)=Ioj+Gj×If(1+βj×Xf×cos(φj(z)+φj))。
If=1かつXf=1かつαi=ATi 2/If
Iij=Ioj+Gj×ATi 2(1+βj×Xi×cos(φi+φj))
Dij=(Iij−Ioj)/(Gj×If) 再スケール調整された強度データ
Dij=αi×(1+βj×Xi×cos(φi+φj))
Dij=αi×(1+βj×Xi×cos(φi(z)+φj))
を用いて軸方向に沿った発光体の位置を決定することが可能である。したがって、i番目の分子の強度に関する3つ以上のデータ値Di0、Di1、Di2、…から、3つの未知の値:αi、Xi、および(最も興味深い)φi(z)を決定するための3つ以上の式が得られる。3つの位相だけが存在する場合、3つの式からこれらの3つの未知量の一意解が得られるであろう。この値、特にφiの値は、たとえば、ニュートン法により解くことが可能である。
χi=Σj[Dij−αi(1+βjcos(φi+φj))]2
tan(φi)≒−ΣjDijsin(φj)/ΣjDijcos(φj)
δi≒λ×φi/(4πn)=λ/(4πn)×atan(ΣjDijsin(φj)/ΣjDijcos(φj))
φi≒4πδ/(nλ)+atan(δ/zR)。
[CA1(z)−PA1]2+[CA2(z)−PA2]2+[CA3(z)−PA3]2+...+[CAN(z)−PAN]2
式中、N=システム中のディテクターの数であり、
CAi(z)=z平面内の特定のサンプル位置に対して校正時に決定されたディテクターiにおける規格化ピーク光エネルギー強度振幅であり、
PAi=現在のPALM画像フレームから決定されたディテクターiにおける規格化ピーク光エネルギー強度振幅である。
δ=2π(Δinner−Δouter)/λ=Δz×(1−cos(θ))×2πn/(λ)。
Δz=δλ/(n(1−cos(θ))。
Claims (8)
- サンプル中の個別に解像可能な光学標識を活性化させる工程と、
光エネルギーが前記活性化された光学標識から複数の方向において放射されるように、前記活性化された光学標識を励起する工程と、
前記光学標識から前記複数の方向に放出される前記光エネルギーを干渉させて複数の出力ビームを生成する工程と、
前記複数の出力ビームに基づいて複数の画像を同時に検出する工程であって、前記複数の画像の各画像は、前記複数の出力ビームの出力ビームの1つに基づく工程と、
前記複数の画像の各画像の強度に基づいて前記光学標識の三次元位置情報を決定する工程と、
を含む、方法。 - 前記複数の方向の各方向からの光エネルギーが、前記複数の方向の少なくとも1つの異なる方向の光エネルギーの光源位相と異なる光源位相を有するように、前記光エネルギーを受け取る工程、
をさらに含み、
前記複数の出力ビームの各出力ビームが、前記複数のビームの残りの出力ビームの位相とは異なる位相を有する、請求項1に記載の方法。 - 前記決定する工程が、前記複数の画像内の前記光学標識の画像に対応する前記複数の画像の各画像の一部分の強度に基づいて三次元位置情報を計算する工程を
含む、請求項1に記載の方法。 - 前記光学標識がスイッチャブルである、請求項1に記載の方法。
- 前記光学標識から放出される光エネルギーが一連の単一光子である、請求項1に記載の方法。
- 前記光学標識がスイッチャブルであり、前記方法が、
前記干渉の前にスイッチャブル光学標識を活性化させる工程と、
前記スイッチャブル光学標識から放出される光エネルギーが、複数の方向の第1の方向および第2の方向に放出されるように、前記活性化の後かつ前記干渉の前に前記スイッチャブル光学標識を励起する工程と、
をさらに含む、請求項1に記載の方法。 - 前記光学標識が点光源として分離可能かつ同定可能である、請求項1に記載の方法。
- 前記光学標識の三次元位置情報を決定する工程は、前記検出された複数の画像の前記強度に基づいてx,y画像平面内の前記光学標識の位置を決定し、前記放出された光エネルギーの間の位相差に基づいて前記x,y画像平面に直交するz方向内の前記光学標識の位置を決定することを含む、請求項1に記載の方法。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US87136606P | 2006-12-21 | 2006-12-21 | |
US60/871,366 | 2006-12-21 | ||
US90830707P | 2007-03-27 | 2007-03-27 | |
US60/908,307 | 2007-03-27 | ||
US11/961,601 | 2007-12-20 | ||
US11/961,601 US7916304B2 (en) | 2006-12-21 | 2007-12-20 | Systems and methods for 3-dimensional interferometric microscopy |
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