JP2013044695A - Measuring method and measuring device of mechanical properties of single cell - Google Patents
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本発明は、原子間力顕微鏡を用いた、単一細胞の力学特性の計測方法と計測装置に関する。 The present invention relates to a method and an apparatus for measuring the mechanical properties of a single cell using an atomic force microscope.
細胞の力学特性は、細胞の機能と密接に関係している。そのため、細胞力学特性はがん細胞等の細胞診断の重要な指標になると考えられている（非特許文献１）。がん細胞に限らず、細胞力学特性から様々な細胞の診断を行うためには、細胞単体を多数計測し、その統計解析を行うシステム・技術の発展が必要不可欠である。 The mechanical properties of cells are closely related to cell function. For this reason, it is considered that the cytodynamic characteristics become an important index for cell diagnosis of cancer cells and the like (Non-patent Document 1). In order to diagnose various cells not only from cancer cells but also from cell dynamics, it is essential to develop systems and technologies that measure a large number of single cells and perform statistical analysis.
多数の細胞を短時間で計測できる有力な方法として、（１）磁気ビーズ法（非特許文献２）、（２）光ストレッチ法（非特許文献３）、そして（３）原子間力顕微鏡法（Atomic Force Microscopy: AFM）（非特許文献４）がある。
磁気ビーズ法は、細胞表面に磁気ビーズを付着させ、変動磁場による磁気ビーズの変位から細胞力学特性を計測する方法である。細胞表面へのビーズの付着位置を制御することができないため、単一細胞間の差異の評価に適さないが、一度に多数の細胞を計測できる利点がある。
光ストレッチ法は、浮遊させた細胞を光の圧力で変形させ、その変形量から細胞の力学特性を計測する方法である。基質に接着して生きている細胞を、基質からはがして計測するため、天然状態の細胞の計測ができない。
原子間力顕微鏡（AFM）はカンチレバー先端の探針を細胞に接触させ、探針に働く力をカンチレバーのたわみ量から計測する。多数の細胞を配列してマイクロアレイを併用することにより、接着細胞の力学特性を精密に計測することができる。
As effective methods that can measure a large number of cells in a short time, (1) magnetic bead method (Non-patent document 2), (2) optical stretch method (Non-patent document 3), and (3) atomic force microscopy ( Atomic Force Microscopy (AFM) (Non-Patent Document 4).
The magnetic bead method is a method in which a magnetic bead is attached to the surface of a cell, and cell dynamic characteristics are measured from the displacement of the magnetic bead due to a varying magnetic field. Since the attachment position of the beads on the cell surface cannot be controlled, it is not suitable for evaluating the difference between single cells, but there is an advantage that a large number of cells can be measured at one time.
The optical stretch method is a method in which suspended cells are deformed by light pressure, and the mechanical properties of the cells are measured from the amount of deformation. Since living cells that adhere to the substrate are peeled off from the substrate, the cells in the natural state cannot be measured.
An atomic force microscope (AFM) measures the force acting on a probe from the amount of deflection of the cantilever by contacting the tip of the cantilever with a cell. By arranging a large number of cells and using a microarray in combination, the mechanical properties of adherent cells can be precisely measured.
細胞は粘弾性体である。したがって、細胞の動的な力学特性は、貯蔵弾性率と損失弾性率と呼ばれる複素弾性率で決定される。生細胞の貯蔵弾性率は周波数のべき乗則に従い、べき乗の値は、おおよそ０．１から０．４程度である（非特許文献５）。細胞力学特性のべき乗応答は、普遍的な性質であるため、複素弾性率の精密計測が細胞診断技術において重要となる。 The cell is a viscoelastic body. Therefore, the dynamic mechanical properties of the cell are determined by a complex elastic modulus called storage elastic modulus and loss elastic modulus. The storage elastic modulus of living cells follows the power law of frequency, and the value of the power is about 0.1 to 0.4 (Non-patent Document 5). Since the power response of cytodynamic properties is a universal property, precise measurement of complex elastic modulus is important in cytodiagnosis technology.
先行技術では、多数細胞計測から得られた貯蔵弾性率の細胞数分布の定量解析は行われていない。その理由は、細胞本来の力学特性と実験誤差とを分離することができないからである。本発明では、細胞診断の有意差検定を行うために必要とされる、細胞数分布の定量解析法と定量解析装置を提案する。 In the prior art, the quantitative analysis of the cell number distribution of the storage elastic modulus obtained from the multi-cell measurement is not performed. The reason is that it is not possible to separate the original mechanical characteristics of the cell from the experimental error. In the present invention, a quantitative analysis method and a quantitative analysis apparatus for cell number distribution, which are required for performing a significant difference test for cytodiagnosis, are proposed.
本発明の第一は、原子間力顕微鏡を用いて多数の細胞を短時間で計測する方法に関する。
［１］原子間力顕微鏡を用いて多数の細胞を計測する方法であって、Ａ）微細加工基板上に個々の細胞を配列し、個々の細胞を自動で位置決めするステップ；Ｂ）配列化した細胞の複素弾性率の周波数特性を計測するステップ；およびＣ）細胞内計測位置または細胞内構造を変化させ、再度、多数細胞の複素弾性率の周波数特性を計測するステップ；を含む方法。
［２］前記原子間力顕微鏡は、細胞の位置を観察できる光学顕微鏡と一体化した、［１］に記載の方法。
［３］前記微細加工基板は、ガラス基板、金属基板、または高分子系基板からなり、細胞の形状を均一化し、細胞を基板表面に配列化するために用いる、［１］〜［２］のいずれかに記載の方法。
［４］前記細胞の複素弾性率の周波数特性は、原子間力顕微鏡を用いた細胞力学応答の周波数変調による計測である、［１］〜［３］のいずれかに記載の方法。
［５］前記細胞内計測位置とは、原子間力顕微鏡カンチレバープローブと細胞との接触位置を変化させて計測する位置である、［１］〜［４］のいずれかに記載の方法。
［６］前記細胞内構造とは、アクチン線維、微小管、中間径フィラメント等の細胞骨格構造を薬剤等の外的な要因により変化させる、［１］〜［５］のいずれかに記載の方法。
The first of the present invention relates to a method for measuring a large number of cells in a short time using an atomic force microscope.
[1] A method for measuring a large number of cells using an atomic force microscope, comprising A) arranging individual cells on a microfabricated substrate and automatically positioning the individual cells; B) arranging the cells. Measuring a frequency characteristic of a complex elastic modulus of a cell; and C) measuring a frequency characteristic of a complex elastic modulus of a large number of cells again by changing an intracellular measurement position or an intracellular structure.
[2] The method according to [1], wherein the atomic force microscope is integrated with an optical microscope capable of observing cell positions.
[3] The microfabricated substrate is made of a glass substrate, a metal substrate, or a polymer substrate, and is used for uniformizing the shape of cells and arranging the cells on the substrate surface. The method according to any one.
[4] The method according to any one of [1] to [3], wherein the frequency characteristic of the complex elastic modulus of the cell is measurement by frequency modulation of a cytodynamic response using an atomic force microscope.
[5] The method according to any one of [1] to [4], wherein the intracellular measurement position is a position measured by changing a contact position between the atomic force microscope cantilever probe and the cell.
[6] The method according to any one of [1] to [5], wherein the intracellular structure changes a cytoskeletal structure such as an actin fiber, a microtubule, or an intermediate filament by an external factor such as a drug. .
本発明の第二は、複素弾性率の細胞数分布を定量解析する方法に関する。
［７］細胞力学特性の細胞数分布を定量解析する方法であって、Ａ）複素弾性率の細胞数分布の平均値、および標準偏差の周波数特性を算出するステップ；Ｂ）細胞内計測位置、または細胞内構造を変化して得られた複素弾性率の周波数特性から実験誤差量を解析するステップ；およびＣ）実験誤差量を考慮して細胞本来の細胞力学特性の標準偏差を算出するステップ；を含む方法。
The second of the present invention relates to a method for quantitatively analyzing the cell number distribution of the complex elastic modulus.
[7] A method for quantitatively analyzing a cell number distribution of cytodynamic characteristics, comprising: A) calculating an average value of the cell number distribution of complex elastic modulus and a frequency characteristic of standard deviation; B) an intracellular measurement position; Or a step of analyzing the experimental error amount from the frequency characteristic of the complex elastic modulus obtained by changing the intracellular structure; and C) a step of calculating the standard deviation of the cell dynamic characteristic inherent to the cell in consideration of the experimental error amount; Including methods.
本発明の第三は、［１］から［６］に記載の原子間力顕微鏡による多数細胞計測、および［７］に記載の細胞数分布の定量解析から、細胞本来の細胞数分布を定量化する装置に関する。 The third aspect of the present invention quantifies the original cell number distribution from the multi-cell measurement by the atomic force microscope described in [1] to [6] and the quantitative analysis of the cell number distribution described in [7]. It is related with the apparatus to do.
本発明により、原子間力顕微鏡計測により得られた細胞の複素弾性率の細胞数分布を定量的に解析することができる。 According to the present invention, the cell number distribution of the complex elastic modulus of cells obtained by atomic force microscope measurement can be quantitatively analyzed.
原子間力顕微鏡を用いて多数細胞計測から細胞本来の偏差（個性）を評価することができる技術であるため、以下の作用・利点がある。
（１）高精度の力計測であり、細胞力学特性の差異を精密に評価できる。
（２）実験条件に依存せず、細胞本来の標準偏差を解析できる。
（３）細胞本来の標準偏差の解析により、個々の細胞の差異を定量化できる。
Since it is a technique that can evaluate the original deviation (individuality) of cells from the measurement of a large number of cells using an atomic force microscope, it has the following actions and advantages.
(1) It is a highly accurate force measurement and can accurately evaluate the difference in cytodynamic properties.
(2) The original standard deviation of the cell can be analyzed without depending on the experimental conditions.
(3) Individual cell differences can be quantified by analyzing the standard deviation of cells.
図１は、本発明の一実施の形態における、原子間力顕微鏡を用いた細胞単体の多数細胞計測の一例を示す図である。微細加工基板上の細胞の位置を観察するために、原子間力顕微鏡と光学顕微鏡とが一体化した装置を用いる。一例として、Ｎｉｋｏｎ社の光学顕微鏡（ＴＥ−２０００）に装着されたＡｓｙｌｕｍ Ｒｅｓｅａｒｃｈ社のＡＦＭ装置（ＭＦＰ−３Ｄ−Ｂｉｏ）がある。 FIG. 1 is a diagram showing an example of multi-cell measurement of a single cell using an atomic force microscope in one embodiment of the present invention. In order to observe the position of the cell on the microfabricated substrate, an apparatus in which an atomic force microscope and an optical microscope are integrated is used. As an example, there is an AFM device (MFP-3D-Bio) manufactured by Asylum Research, which is mounted on a Nikon optical microscope (TE-2000).
培養ディッシュ上で培養した細胞を微細加工基板上に播種・培養する。可能な限り、細胞を基板上に配列し、その形状を均一にする。細胞種は、線維芽細胞、上皮細胞、内皮細胞、神経細胞、骨格筋細胞、およびそれらに関連する細胞である。 Cells cultured on the culture dish are seeded and cultured on a microfabricated substrate. As much as possible, arrange the cells on the substrate and make the shape uniform. Cell types are fibroblasts, epithelial cells, endothelial cells, neurons, skeletal muscle cells, and related cells.
原子間力顕微鏡カンチレバープローブを細胞に圧入し、カンチレバーもしくは細胞接着基板をある周波数で振動させる。振動周波数に対するカンチレバーの振幅および位相をロックイン検波器で計測し、複素弾性率（貯蔵弾性率と損失弾性率）を求める。この計測を、振動周波数を変化させながら行い、複素弾性率の周波数特性を測定する。この細胞測定後、隣の細胞を同様の方法で計測して多数細胞の複素弾性率のデータを得る。次に、細胞内計測位置または細胞内構造を変化させ、再度、上記と同様の計測を行う。 An atomic force microscope cantilever probe is pressed into a cell, and the cantilever or cell adhesion substrate is vibrated at a certain frequency. The amplitude and phase of the cantilever with respect to the vibration frequency are measured with a lock-in detector, and the complex elastic modulus (storage elastic modulus and loss elastic modulus) is obtained. This measurement is performed while changing the vibration frequency, and the frequency characteristic of the complex elastic modulus is measured. After this cell measurement, neighboring cells are measured by the same method to obtain data of complex elastic modulus of many cells. Next, the intracellular measurement position or the intracellular structure is changed, and the same measurement as described above is performed again.
図２に示すように、複素弾性率の細胞数分布は対数正規分布に従う。細胞数分布の平均値および標準偏差の周波数特性を算出する。 As shown in FIG. 2, the cell number distribution of the complex elastic modulus follows a lognormal distribution. Calculate frequency characteristics of mean value and standard deviation of cell number distribution.
生細胞の貯蔵弾性率は周波数のべき乗則に従う。図３aは、貯蔵弾性率の周波数特性を模式的に示した図である。貯蔵弾性率は、周波数の増加とともにべき乗則で増大する。べき指数の値は、細胞内測定位置や細胞内構造の計測条件に依存して変化する。計測条件が異なる計測データのべき乗曲線は点Ａ（Ｆ,ｇ）で交差する。点Ａの周波数Ｆにおいて、細胞力学特性は、計測条件に依らずに一定の値をもつ。 The storage modulus of living cells follows the power law of frequency. FIG. 3a is a diagram schematically showing the frequency characteristic of the storage elastic modulus. The storage modulus increases with a power law as the frequency increases. The value of the power index changes depending on the measurement position of the intracellular measurement position and the intracellular structure. The power curves of the measurement data with different measurement conditions intersect at point A (F, g). At the frequency F at point A, the cytodynamic characteristics have a constant value regardless of the measurement conditions.
図３ａの関係から、貯蔵弾性率の細胞数分布の標準偏差の規則性が導かれる。図３bは、貯蔵弾性率の標準偏差の周波数特性を模式的に示した図である。標準偏差の大きさは、計測条件に依存して変化し、周波数の減少関数になる。計測条件が異なる計測データが交差する点Ｂが存在する。交差点の周波数はＦであり、標準偏差はゼロである。 From the relationship of FIG. 3a, the regularity of the standard deviation of the cell number distribution of the storage modulus is derived. FIG. 3b is a diagram schematically showing the frequency characteristic of the standard deviation of the storage elastic modulus. The magnitude of the standard deviation varies depending on the measurement conditions and becomes a frequency decreasing function. There is a point B where measurement data with different measurement conditions intersect. The frequency of the intersection is F and the standard deviation is zero.
図３に示した細胞の複素弾性率の関係は、ＡＦＭ計測に制限されるものではない。従って、図３を考慮した解析法は、ＡＦＭ以外の細胞力学計測法にも適用できる。 The relationship of the complex elastic modulus of the cell shown in FIG. 3 is not limited to AFM measurement. Therefore, the analysis method considering FIG. 3 can also be applied to cell mechanics measurement methods other than AFM.
図４は、ＡＦＭ計測による算出された貯蔵弾性率の標準偏差Ｗを模式的にグラフ表示した図である。異なる細胞サンプルの結果の交点Ｂにおいて、標準偏差は正の値ｓをもつ。図３ａより、この値はゼロでなければならない。したがって、数値ｓは細胞本来の偏差ではなく、主に、それ以外の実験誤差に起因する。このように、Ｖ＝Ｗ−ｓの関係式を用いて、細胞本来の偏差を算出できる。 FIG. 4 is a graph schematically showing the standard deviation W of the storage elastic modulus calculated by AFM measurement. At the intersection B of the results of different cell samples, the standard deviation has a positive value s. From FIG. 3a, this value must be zero. Therefore, the numerical value s is not due to the original deviation of the cell but mainly due to other experimental errors. Thus, the original cell deviation can be calculated using the relational expression of V = W−s.
図５は、微細加工基板上に配列化したマウスの線維芽細胞のＡＦＭ計測の結果を示している。通常の細胞とアクチン骨格を破壊した細胞の貯蔵弾性率は、交点（Ｆ，ｇ）で一致する。また、この周波数Ｆにおいて、貯蔵弾性率の標準偏差Ｗは正の値ｓをもつ。 FIG. 5 shows the results of AFM measurement of mouse fibroblasts arranged on a microfabricated substrate. The storage elastic moduli of normal cells and cells that have destroyed the actin skeleton coincide at the intersection (F, g). Further, at this frequency F, the standard deviation W of the storage elastic modulus has a positive value s.
図６は、異なる計測結果から細胞本来の標準偏差Ｖを解析した図である。異なる細胞サンプルであっても計測条件が同じ（黒塗りの三角と四角）である場合は、Ｖの値はほぼ一致する。一方で、計測条件が異なるデータ（白抜きの三角と四角）は、他のデータと大きく異なる。このように、細胞力学の偏差を定量的に解析することができる。 FIG. 6 is a diagram in which the standard deviation V of the cell is analyzed from different measurement results. Even if different cell samples have the same measurement conditions (black triangles and squares), the values of V are almost the same. On the other hand, data with different measurement conditions (open triangles and squares) are significantly different from other data. In this way, deviations in cell mechanics can be quantitatively analyzed.
図７は、細胞力学特性の細胞数分布を定量化する装置を示している。装置はＡＦＭ装置部とデータ解析部からなる。 FIG. 7 shows an apparatus for quantifying the cell number distribution of cytodynamic properties. The apparatus includes an AFM apparatus unit and a data analysis unit.
ＡＦＭ装置部において、［１］から［６］に記載の多数細胞の複素弾性率のデータを取得する。データ解析部において、Ａ）複素弾性率の細胞数分布を導出するステップ；Ｂ）細胞分布の周波数特性を算出するステップ；Ｃ）実験誤差量を解析するステップ；およびＤ）細胞本来の標準偏差を算出するステップ；を含む装置である。 In the AFM apparatus unit, the complex elastic modulus data of the large number of cells described in [1] to [6] is acquired. In the data analysis unit, A) a step of deriving the cell number distribution of the complex elastic modulus; B) a step of calculating the frequency characteristics of the cell distribution; C) a step of analyzing the experimental error amount; and D) the standard deviation of the cell. Calculating the apparatus.
本発明により、細胞本来の力学特性と実験誤差とが含まれる細胞力学統計分布から、前者のみを抽出することができる。従って、細胞単体の力学特性を比較することにより、がん細胞等の細胞診断が可能になり、細胞力学特性の統計解析が必要とされる産業全般に利用できる。 According to the present invention, only the former can be extracted from a cell mechanics statistical distribution including the original mechanical characteristics and experimental errors. Therefore, by comparing the mechanical properties of single cells, cell diagnosis of cancer cells and the like becomes possible, and it can be used for all industries that require statistical analysis of cell dynamic properties.
１００ ＡＦＭカンチレバー
２００ 微細加工基板上の配列細胞
100 AFM cantilever 200 arrayed cells on microfabricated substrate
Claims (8)
Ａ）微細加工基板上に個々の細胞を配列し、個々の細胞を自動で位置決めするステップ；
Ｂ）配列化した細胞の複素弾性率の周波数特性を計測するステップ；
および
Ｃ）細胞内計測位置または細胞内構造を変化させ、再度、多数細胞の複素弾性率の周波数特性を計測するステップ；を含む方法。 A method for measuring a large number of cells using an atomic force microscope,
A) arranging individual cells on a microfabricated substrate and automatically positioning the individual cells;
B) measuring the frequency characteristic of the complex elastic modulus of the arranged cells;
And C) changing the intracellular measurement position or intracellular structure, and again measuring the frequency characteristics of the complex elastic modulus of a large number of cells.
Ａ）複素弾性率の細胞数分布の平均値、および標準偏差の周波数特性を算出するステップ；
Ｂ）細胞内計測位置、または細胞内構造を変化して得られた複素弾性率の周波数特性から実験誤差量を解析するステップ；
および
Ｃ）実験誤差量を考慮して細胞本来の細胞力学特性の標準偏差を算出するステップ；を含む方法。 A method for quantitative analysis of cell number distribution of cytodynamic properties,
A) calculating the mean value of the cell number distribution of the complex elastic modulus and the frequency characteristic of the standard deviation;
B) Analyzing the amount of experimental error from the frequency characteristics of the complex elastic modulus obtained by changing the intracellular measurement position or the intracellular structure;
And C) calculating a standard deviation of the cell's original cytodynamic properties in consideration of the amount of experimental error.
Ａ）請求項１から６に記載の方法を含む原子間力顕微鏡装置部；および
Ｂ）請求項７に記載の方法を含むデータ解析部、を有する装置。
An apparatus for quantifying cell number distribution of cytodynamic properties,
An apparatus comprising: A) an atomic force microscope apparatus unit including the method according to claim 1; and B) a data analysis unit including the method according to claim 7.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016014590A (en) * | 2014-07-02 | 2016-01-28 | 国立大学法人北海道大学 | Measuring method and measuring system of complex elastic modulus of cell |
| CN107543939A (en) * | 2017-07-19 | 2018-01-05 | 天津大学 | A kind of method for assessing pure titanium material surface osteogenic cell Osteoblast Differentiation ability |
| WO2019112414A1 (en) * | 2017-12-04 | 2019-06-13 | Instituto Politécnico Nacional | Process using atomic force microscopy for mass physical and mechanical analysis in materials, biomaterial arrangements and structures |
-
2011
- 2011-08-26 JP JP2011184403A patent/JP2013044695A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2016014590A (en) * | 2014-07-02 | 2016-01-28 | 国立大学法人北海道大学 | Measuring method and measuring system of complex elastic modulus of cell |
| CN107543939A (en) * | 2017-07-19 | 2018-01-05 | 天津大学 | A kind of method for assessing pure titanium material surface osteogenic cell Osteoblast Differentiation ability |
| WO2019112414A1 (en) * | 2017-12-04 | 2019-06-13 | Instituto Politécnico Nacional | Process using atomic force microscopy for mass physical and mechanical analysis in materials, biomaterial arrangements and structures |
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