WO1998041820A1 - Procede et appareil de mesure des proprietes et des processus des cellules au niveau de surfaces - Google Patents

Procede et appareil de mesure des proprietes et des processus des cellules au niveau de surfaces Download PDF

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Publication number
WO1998041820A1
WO1998041820A1 PCT/SE1998/000485 SE9800485W WO9841820A1 WO 1998041820 A1 WO1998041820 A1 WO 1998041820A1 SE 9800485 W SE9800485 W SE 9800485W WO 9841820 A1 WO9841820 A1 WO 9841820A1
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WIPO (PCT)
Prior art keywords
cells
crystal
sensor
crystal sensor
damping
Prior art date
Application number
PCT/SE1998/000485
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English (en)
Swedish (sv)
Inventor
Michael Rodahl
Anatol Krozer
Bengt Kasemo
Fredrik Höök
Claes Fredriksson
Daniella Steel
Original Assignee
Q-Sense Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Q-Sense Ab filed Critical Q-Sense Ab
Priority to AU64318/98A priority Critical patent/AU6431898A/en
Publication of WO1998041820A1 publication Critical patent/WO1998041820A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01G—WEIGHING
    • G01G3/00—Weighing apparatus characterised by the use of elastically-deformable members, e.g. spring balances
    • G01G3/12—Weighing apparatus characterised by the use of elastically-deformable members, e.g. spring balances wherein the weighing element is in the form of a solid body stressed by pressure or tension during weighing
    • G01G3/13—Weighing apparatus characterised by the use of elastically-deformable members, e.g. spring balances wherein the weighing element is in the form of a solid body stressed by pressure or tension during weighing having piezoelectric or piezoresistive properties
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N5/00—Analysing materials by weighing, e.g. weighing small particles separated from a gas or liquid

Definitions

  • the invention relates to a method for measuring properties and/or processes of one or more cells, including also organisms, which interact with a surface, by measuring the damping, e.g. the dissipation factor of a piezoelectric crystal sensor, preferably of the QCM (Quartz Crystal Microbalance) type.
  • the damping e.g. the dissipation factor of a piezoelectric crystal sensor, preferably of the QCM (Quartz Crystal Microbalance) type.
  • the invention relates to a method for measuring in real time properties and/or processes of one or more cells, interacting with at least one surface of at least one piezoelectric crystal sensor, where one side of said crystal sensor forms a sensor surface, which is exposed to a liquid, containing said cells, and to an apparatus for such a measurement, including at least one piezoelectric crystal sensor with crystal and a drive circuit to put the crystal in oscillation and a device for exposing one side of the crystal to a liquid, containing the cells.
  • a crystal sensor of the QCM type is an extremely sensitive balance, intended for weighing small amounts of material added to or removed from one or more of its electrodes, or thin layers applied to these electrodes.
  • the crystal sensor commonly consists of a single-crystal disc of a piezoelectric material coated with at least two electrodes.
  • the crystal is preferabl) made of quartz but other piezoelectric materials can also be used.
  • the crystal is preferably cut in so-called AT-, SC-, or BT-cuts.
  • AT-, SC-, or BT-cuts See references [1 -4J.
  • Such a crystal can oscillate in shear mode with amplitudes of approximately 1 -10 nm and with the fundamental frequency:
  • d is the thickness of the crystal.
  • d is the thickness of the crystal.
  • d «0.17 mm then/ O MHz.
  • the oscillation arises when an AC field is applied perpendicularly to the crystal surface.
  • the frequency of the AC field should be centred around one of the resonant frequencies of the crystal.
  • the electrodes are commonly applied on each of the crystal faces by vapour deposition.
  • the electrodes are then electrically connected to an external oscillator circuit/drive circuit to be able to put the crystal in oscillation.
  • This device can measure ver small mass changes on the electrodes of the quartz crystal, of the order of 1 ng/cm 2 or. under favorable conditions, even less.
  • the shift in resonant frequency, f is proportional to the change in mass, Am, i.e.
  • Equation (2) presupposes that the mass, represented by Am, is rigidly attached to, evenly distributed on the electrode and follows the oscillation of the crystal sensor without dissipative losses, i.e., without damping.
  • Other measures, such as oscillation amplitude or impedance of the crystal sensor, can also be used.
  • equation (2) is not generally valid if the deposited mass consists of a viscous material and/or is unevenly distributed over the mass-sensitive area of the crystal, e.g., when the deposited mass is a group of cells. In such cases, a given deposited mass may give rise to different frequency shifts, which means that a certain frequency shift may correspond to different masses. In these cases it is thus of limited value to measure only changes in the resonant frequency.
  • the purpose of the present invention is, thus, to enable measurement in real time of qualitative properties and/or processes of one or more cells, including also organisms, which interact with a surface.
  • changes in the resonant frequency of the crystal sensor caused by said interaction are also measured and the relation between changes in the damping and resonant frequency of the sensor is determined.
  • the damping or the combination of changes in the damping and resonant frequency according to this method can be used for characterization of the interaction.
  • the sensitivity for changes, both in damping and resonant frequency varies according to a gaussian distribution over the electrode surface with its maximum in the centre and with approximately the same width as the electrode.
  • the high degree of specificity and sensitivity obtained are the properties that enable the method to be used for characterization of cells interacting with surfaces in a plurality of different situations.
  • properties and processes that can be measured are cell adhesion, cell detachment, cell fission, and cell secretion of adhesion proteins, enzymes or mucus.
  • internal cell structural changes as a response to external stimuli, such as temperature, surface chemistry, surface morphology, surface coatings and/or additions to the cell medium can be determined.
  • the invention also relates to an apparatus for measuring in real time properties and/or processes of one or more cells, including at least one piezoelectric crystal sensor with crystal and drive circuit to put the crystal in oscillation and a device designed to expose one side of the crystal to a liquid, containing the cells, and a measuring unit arranged to measure changes in the damping of the crystal during the interaction of the cells with the crystal sensor surface.
  • the sensor surface should be designed so that the cell properties and/or processes can be studied. This surface should be suitable with respect to coating, surface chemistry and morphology.
  • the measuring unit is designed to measure also the resonant frequency of the crystal sensor, or changes in this frequency during the interaction of the cells with the ciystal sensor surface.
  • D damping
  • D and / ' measure different properties of the characterized system but by relating D to /the dependence on the number of cells and their positions on the crystal sensor surface can be qualitatively eliminated.
  • the measuring unit is designed to measure the resonant frequency and/or the damping of the crystal sensor at the fundamental frequency as well as at overtones and/or at different oscillation amplitudes.
  • Additional fingerprints are thus obtained by exciting the crystal at its overtones (3rd, 5th, etc.), and recording the Incurve at each overtone. Moreover, it is possible to use different crystal cuts simultaneously, not only the AT-cut, and record the £ ) /-curve for the different cuts. Furthermore, the D/-curve can be measured for different oscillation amplitudes.
  • Fig. 1 schematically depicts an embodiment of a measurement chamber of the apparatus according to the invention
  • Figs. 2-9 show the response of the crystal sensor and the so called /-curve for various depositions of cells on the sensor surface.
  • Fig. 1 shows schematically a suitable measurement chamber of the apparatus according to the invention.
  • a crystal sensor 1 is mounted in the measurement chamber which has a window 2, allowing visual inspection of the cells on the sensor surface of the crystal.
  • Channels 3, 4, 5 allow in- or outlet of liquid and/or injection of cells.
  • the measurement chamber is temperature stabilized and the crystal sensor 1 includes a 5 MHz AT-cut quartz crystal. Furthermore, there is an appropriate drive circuit to put the crystal in oscillation and a measuring unit to measure the damping and resonant frequency and/or changes in these quantities.
  • the drive circuit and the measuring unit are not described in greater detail here, since these devices are known per se..
  • the dissipation factor As a measure of the damping the dissipation factor is consistantly used.
  • Fig. 2 shows to the left the response of the crystal sensor to the deposition of some hundred CHO cells on the sensor surface, which consists of hydrophobic (untreated) polystyrene coated with serum proteins, in a medium containing serum.
  • the /curve for the corresponding data is shown to the right of the figure.
  • Fig. 3 shows to the left the response of the crystal sensor to the deposition of some hundred CHO cells on the sensor surface, which consists of hydrophilic (UV/ozone treated) polystyrene coated with serum proteins, in a medium containing serum.
  • the D/curve for the corresponding data is shown to the right of the figure with dashed lines to make clear two linear regimes in the response.
  • Fig. 4 shows to the left the response of the crystal sensor to the deposition of some hundred MKE cells on the sensor surface, which consists of hydrophobic (untreated) polystyrene, in serum-free medium.
  • the Df-curve for the corresponding data is shown to the right of the figure with a second order polynomial function fitted to the data in order to make clear the decreasing trend of the curve.
  • Fig. 5 shows to the left the response of the crystal sensor to the deposition of some hundred MKE cells on the sensor surface, which consists of hydrophilic (UV/ozone treated) polystyrene, in a serum-free medium.
  • the £ ) /curve for the corresponding data is shown to the right in the figure with a second order polynomial function fitted to the data in order to make clear the increasing trend of the curve.
  • Fig. 6 shows to the left the response of the crystal sensor to the deposition of approximately 2000 neutrophils on the sensor surface, which consists of hydrophobic (untreated) polystyrene, in KRG-buffered medium.
  • the /-curve for the corresponding data is shown to the right in the figure.
  • Fig. 7 shows to the left the response of the crystal sensor to the deposition of aproximately 2000 neutrophils on the sensor surface, which consists of hydrophobic (untreated) polystyrene, coated by IgG, in a KRG-buffered medium.
  • the Z ) / curve for the corresponding data with phase I and phase II of the response indicated is shown to the right in the figure.
  • Fig. 8 shows to the left the response of the crystal sensor to the deposition of aproximately 2000 neutrophils on the sensor surface, which consists of hydrophobic (untreated) polystyrene, coated by HSA, in KRG-buffered medium.
  • the Z)/ : curve for the corresponding data with phase I and phase II of the response indicated is shown to the right in the figure.
  • Fig. 9 shows to the left the response of the crystal sensor to a layer of human LSI 74T cells cultured 24 hours on the sensor surface, which consists of hydrophilic (UV/ozone treated) polystyrene. The cells are stimulated to mucus secretion by carbachol. The Z)/-curve for the corresponding data is shown to the right in the figure.
  • Example 1
  • CHO (Chinese Hamster Ovary) cells were cultured in a laboratory, rinsed and then kept in suspension in a serum free tissue culture medium. Small amounts of this cell suspension were injected shortly after the preparation into the temperature stabilized measurement chamber (Fig. 1).
  • the measurement chamber was filled with a cell culture medium containing serum and in the chamber a polystyrene coated crystal sensor was mounted that had been exposed to serum proteins from the cell culture medium for more than 1 hour. The adsorption of the protein layer on the polystyrene surface was measured in situ with the crystal sensor equipment and was found to be in equilibrium at that time. The deposition of cells was monitored by a microscope through the window 2 of the measurement chamber simultaneously with measurements of changes in the resonant frequency and dissipation factor of the crystal sensor.
  • MKE (Monkey Kidney Epithelial) cells of the cos-7 type were cultivated in a laboratory, rinsed and then kept in suspension in a serum free cell culture medium. Small amounts of this cell suspension were injected shortly after preparation into the temperature stabilized measurement chamber (Fig. 1). In this case the measurement chamber was filled with a serum free cell culture medium and in the chamber a polystyrene coated crystal sensor 1 was mounted. The deposition of cells was monitored by a microscope through the window 2 of the measurement chamber simultaneously with measurements of changes in the resonant frequency and the dissipation factor of the crystal sensor 1.
  • the resonant frequency immediately decreases at the cell deposition, while the dissipation factor increases to various extent relative to the frequency change.
  • the slope of the /-curve differs drastically from the slope of the corresponding curve in Example 1, where the cells were deposited on surfaces coated with serum proteins. This depends on the fact that the cells in the serum-free cases themselves actively secrete adhesion proteins in order to be able to attach to the surface. These proteins have a characteristic dissipation/frequency relation different from that of the cells themselves and can therefore be identified.
  • the increase in the slope of the curve during the cell adhesion to the hydrophilic surface is due to increased dissipation factor caused by cell attachment in the same manner as in Example 1.
  • the hydrophobic surface is not able to stimulate cell attachment to the same extent, which is seen in the decreasing slope of the /curve. A similar behaviour is found also for CHO cells deposited on these two surfaces in a serum-free environment.
  • Neutrophils were separated from human blood, rinsed and after that kept in a suspension in Krebs-Ringer Phosphate buffer. Small amounts of this cell suspension were injected shortly after preparation into the temperature-stabilized measurement chamber (Fig. 1).
  • the measurement chamber was filled with phosphate buffered saline (PBS) solution supplemented with magnesium and glycose and in the chamber a polystyrene coated crystal sensor 1 was mounted. In two cases the crystal sensor surface was exposed before the cell deposition to Immunoglobuline G (IgG) or human serum albumin (HSA) during 30 minutes. The adsorption of the protein layer on to the polystyrene surface was measured in situ with the crystal sensor equipment and was found to be in equilibrium at that time.
  • PBS phosphate buffered saline
  • IgG Immunoglobuline G
  • HSA human serum albumin
  • the deposition of cells was monitored by a microscope through the window 2 of the measurement chamber simultaneously with measurements of changes in the resonant frequency and dissipation factor of the crystal sensor. Said measurements were performed for three different crystal sensor surfaces, under otherwise identical conditions, namely (i) untreated (hydrophobic) polystyrene (Fig. 7), (ii) polystyrene coated with IgG (Fig. 8), and (iii) polystyrene coated with HSA (Fig. 9).
  • the dissipation energy increases and the resonant frequency drops immediately after the deposition due to cell attachment and cell spreading (Fig. 6).
  • the neutrophils are activated by Fc-receptors at the deposition on the IgG surface. This results in a clear difference in the crystal sensor response, which can be divided into two phases, I and II, before and after the turning point of the crystal sensor signals, respectively (Fig. 7).
  • phase I will be discussed.
  • the degree of cell spreading and the associated reorganisation of actin in the cytoskeleton of the cell can be correlated to the activity of neutrophil oxidase, which involves activation of b 2 integrins, responsible for the attachment of neutrophils [10-12]. All these factors affect the rigidity of the cell and the ability to transfer vibrational energy via integrins to the cytoskeleton and therefore affect the dissipation factor. It is clear from the data that the increase in the dissipation factor relative to the decrease in the resonant frequency in phase I is approximately 5 times larger than in case 2, where the Fc-receptors are involved, than for neutrophils deposited on pure polystyrene.
  • the kinetics of the adhesion of neutrophils on HSA is also notably slower than for the other two cases.
  • the turning point for the crystal sensor signals, that separates phase I and phase II, is reached after less than 10 minutes on IgG but not until after around 20 minutes on HSA.
  • Phase II where the dissipation factor decreases and the resonant frequency increases, is caused by the desorption of IgG and HSA from the crystal sensor surface due to the fact that degrading enzymes and oxidative substances (for example hydrogen peroxide and superoxide) are secreted naturally by neutrophils. These do not affect the pure polystyrene surface, and therefore this phase cannot be observed in case 1. In phase II it is clearly observed that proteins have desorbed from the surface since the resonant frequency towards the end of the measurement is larger than before the neutrophils were deposited.
  • degrading enzymes and oxidative substances for example hydrogen peroxide and superoxide
  • Example 1 -3 show that the present invention is well suited as a tool for evaluation of the influence of surfaces and liquids on, e.g. medical implants or other biomaterials.
  • Example 4
  • Human colon cells (LS 174T) were cultured for 24 hours directly on a polystyrene coated (UV/ozone treated) crystal sensor in an incubator.
  • the crystal sensor 1 with the cells thereon was mounted in the measurement chamber (Fig. 1 ) and the chamber was filled with a serum- free cell culture medium.
  • a small amount of Carbachol was injected, which act as a stimulus for mucus secretion (exocytosis), whereupon changes in the resonant frequency and dissipation factor of the crystal sensor 1 were measured (Fig. 9).
  • the response begins approximately 2-3 minutes after the addition of stimulus.
  • An increase of the resonant frequency indicates that the total contact area of the cells with the ciystal sensor surface decreases (contraction), possibly in combination with changes in the internal structure.
  • a period of increasing dissipation factor and decreasing resonant frequency follows.
  • a preliminary inte ⁇ retation is that this is caused by mucus secreted by the cells and gradually replaces the cell culture medium at the crystal sensor surface around the cells. The mucus has a higher density and viscosity and therefore results in increased load.

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  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Piezo-Electric Or Mechanical Vibrators, Or Delay Or Filter Circuits (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention porte sur un procédé de mesure en temps réel des propriétés et/ou des processus d'une ou plusieurs cellules ayant une interaction avec au moins une surface d'au moins un capteur comprenant un cristal piézoélectrique (1). Un côté de ce capteur comprenant un cristal piézoélectrique forme une surface qui est exposée à un liquide et qui contient les cellules, l'amortissement du capteur piézoélectrique étant mesuré pendant et/ou après qu'une ou plusieurs cellules viennent en contact avec la surface du capteur. L'appareil permettant d'effecteur ces mesures comprend au moins un capteur piézoélectrique (1) comportant un cristal et un circuit d'attaque destiné à faire osciller le cristal, et un dispositif permettant d'exposer à un liquide un côté du cristal contenant les cellules. L'unité de mesure permet de mesurer l'amortissement du cristal et/ou les variations de l'amortissement lors de l'interaction des cellules avec la surface du cristal.
PCT/SE1998/000485 1997-03-17 1998-03-17 Procede et appareil de mesure des proprietes et des processus des cellules au niveau de surfaces WO1998041820A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64318/98A AU6431898A (en) 1997-03-17 1998-03-17 Method and apparatus for measuring properties and processes of cells at surfaces

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9701007A SE9701007L (sv) 1997-03-17 1997-03-17 Förfarande vid en piezoelektrisk kristallmikrovågsmätning
SE9701007-8 1997-03-17

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055613A1 (fr) * 1999-03-17 2000-09-21 Q-Sense Ab Procede d'examen des proprietes chimico-physiques d'un film mince
WO2004042370A1 (fr) * 2002-11-07 2004-05-21 Avl List Gmbh Procede pour determiner des parametres physiques ou chimiques d'une couche de matiere de faible epaisseur
WO2011033285A1 (fr) 2009-09-18 2011-03-24 Cambridge Enterprise Limited Appareil et procédé permettant de détecter des espèces cibles dans un analyte
JP2019530442A (ja) * 2016-08-29 2019-10-24 湖南農業大学Ｈｕｎａｎ Ａｇｒｉｃｕｌｔｕｒａｌ Ｕｎｉｖｅｒｓｉｔｙ 細胞牽引力のリアルタイム定量的測定法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1980002158A1 (fr) * 1979-04-09 1980-10-16 Minnesota Mining & Mfg Methode de detection de cellules adherentes
EP0215669A2 (fr) * 1985-09-17 1987-03-25 Seiko Instruments Inc. Diagnostique et procédé d'analyse de composés biochimiques, microbes et cellules
US4999284A (en) * 1988-04-06 1991-03-12 E. I. Du Pont De Nemours And Company Enzymatically amplified piezoelectric specific binding assay
GB2242523A (en) * 1990-03-30 1991-10-02 Leybold Inficon Inc Measuring and controlling deposition on a piezoelectric monitor crystal
US5135852A (en) * 1989-07-25 1992-08-04 E. I. Du Pont De Nemours And Company Piezoelectric cell growth biosensing method using polymer-metabolic product complex interactions
US5201215A (en) * 1991-10-17 1993-04-13 The United States Of America As Represented By The United States Department Of Energy Method for simultaneous measurement of mass loading and fluid property changes using a quartz crystal microbalance
SE504199C2 (sv) * 1995-05-04 1996-12-02 Bengt Kasemo Anordning vid mätning av resonansfrekvens och/eller dissipationsfaktor hos en piezoelektrisk kristallmikrovåg

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1980002158A1 (fr) * 1979-04-09 1980-10-16 Minnesota Mining & Mfg Methode de detection de cellules adherentes
EP0215669A2 (fr) * 1985-09-17 1987-03-25 Seiko Instruments Inc. Diagnostique et procédé d'analyse de composés biochimiques, microbes et cellules
US4999284A (en) * 1988-04-06 1991-03-12 E. I. Du Pont De Nemours And Company Enzymatically amplified piezoelectric specific binding assay
US5135852A (en) * 1989-07-25 1992-08-04 E. I. Du Pont De Nemours And Company Piezoelectric cell growth biosensing method using polymer-metabolic product complex interactions
GB2242523A (en) * 1990-03-30 1991-10-02 Leybold Inficon Inc Measuring and controlling deposition on a piezoelectric monitor crystal
US5201215A (en) * 1991-10-17 1993-04-13 The United States Of America As Represented By The United States Department Of Energy Method for simultaneous measurement of mass loading and fluid property changes using a quartz crystal microbalance
SE504199C2 (sv) * 1995-05-04 1996-12-02 Bengt Kasemo Anordning vid mätning av resonansfrekvens och/eller dissipationsfaktor hos en piezoelektrisk kristallmikrovåg

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SENSORS AND ACTUATORS, Volume 54, June 1996, MICHAEL RODAHL et al., "On Themeasurement of Thin Liquid Overlayers with the Quartz-Crystal Microbalance", pages 448-456. *
SENSORS AND ACTUATORS, Volume B 37, November 1996, MICHAEL RODAHL et al., "Frequency and Dissipation-Factor Responses to Localized Liquid Deposits on a QCM Electrode", pages 111-116. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055613A1 (fr) * 1999-03-17 2000-09-21 Q-Sense Ab Procede d'examen des proprietes chimico-physiques d'un film mince
WO2004042370A1 (fr) * 2002-11-07 2004-05-21 Avl List Gmbh Procede pour determiner des parametres physiques ou chimiques d'une couche de matiere de faible epaisseur
WO2011033285A1 (fr) 2009-09-18 2011-03-24 Cambridge Enterprise Limited Appareil et procédé permettant de détecter des espèces cibles dans un analyte
JP2019530442A (ja) * 2016-08-29 2019-10-24 湖南農業大学Ｈｕｎａｎ Ａｇｒｉｃｕｌｔｕｒａｌ Ｕｎｉｖｅｒｓｉｔｙ 細胞牽引力のリアルタイム定量的測定法

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AU6431898A (en) 1998-10-12
SE9701007L (sv) 1998-09-18

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